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HYBOT-PLUS MANUAL

Introduction

Hydrogen bonding plays a fundamental role in many chemical and biological problems, from the study of water’s properties to the binding of base pairs in the DNA double helix. The energy and structural properties of the H-bond are intermediate to those of the classical covalent bond and van der Waals interactions. Conditionally, hydrogen bonding involves energies up to 60 kJ/mole, and bond lengths as short as 0.2 nm.

Approaches for studying hydrogen bonds can be divided into two groups: quantum chemical calculations and empirical methods. The use of ab initio calculations allows the energy and geometric structures of small molecules to be described with an accuracy approaching those of experimental results. However, a similar treatment of large molecules is not yet practical. Here we will be concerned only with empirical methods, exclusively correlation models.

HYBOT includes a correlation model founded on its thermodynamic database (the enthalpies and free energies of H-bond formation). This model estimates the relative proton acceptor and proton donor strengths of compounds in the form of factors using a common H-bond scale. These factors have been used successfully to discover significant relationships between chemical structure and biological activity. Of particular importance is the influence that H-bonding has upon lipophilicity, a physical property that plays an important role in drug transport in biological systems and in drug-receptor binding. Lipophilicity is usually expressed as the logarithm of a compound’s distribution coefficient between n-octanol and water (log P).

Calculation Methods

Factor calculations based on experimental thermodynamic data

Thermodynamic data form the quantitative basis for the one-centre hydrogen bond model discussed in this section. A complete thermodynamic description of hydrogen bonding involves free energy (D G), enthalpy (D H) and entropy (D S) which are related to each other by the following equation:

D G = D H - TD S (1)

where T is the absolute temperature in degrees Kelvin (° K).

A simple multiplicative expression for estimating H-bond enthalpy was proposed in pioneering works by Sherry and Purcell [1] and by Iogansen [2]. This approach is based on the constancy and mutual independence of donor and acceptor factors of interacting molecules. In 1982 we proposed [3,4] a common hydrogen bond enthalpy scale based on this multiplicative principle. In this case, the enthalpy of H-bond formation is proportional to the product of the factor value for the H-bond donor (Ed) and that for the H-bond acceptor (Ea):

D H = k1EdEa (2)

where k1 is the proportionality constant. The donor factor (Ed) and the acceptor factor (Ea) are determined for various molecules based on their enthalpies in different combinations with other molecules, and by scaling the results to the system phenol-hexamethylphosphoramide (HMPA) in tetrachloromethane (CCl4) at 298 ° K. In this system the H-bond donor factor (that for phenol) was set as Ed = -2.50, and the H-bond acceptor factor (that for HMPA) set as Ea = 2.50 to cover a practical range of values.

A few years later we proposed [5,6] a similar hydrogen bond free energy scale where free energy of H-bond is calculated on the basis of next equation:

D G = k’1Cd Ca + k’o (3)

where Cd and Ca are respectively the H-bond free energy donor and acceptor factors. The system phenol-HMPA in CCl4 was chosen as the reference standard; the H-bond free energy factors Cd and Ca were set at -2.50 (phenol) and 4.00 (HMPA) respectively.

An analogous method for calculating equilibrium constants (K) for H-bonding was proposed independently by Abraham at al [7]:

log K = k"1a b + k"o (4)

where a is proportional to H-bond acidity and b is proportional to H-bond basicity.

We correlated experimental with calculated values of the enthalpies and free energies for approximately 3000 H-bond complexes using the multiplicative approach. Our results are presented in [9] and are summarized as follows:

D Hcalc = -0.49(± 0.29) + 0.99(± 0.08)D Hexp (5)

n = 2787 r = 0.970 s = 2.40 F = 44350

where n is the number of data points, r the correlation coefficient, s the standard error of the estimate, and F the variance ratio. The numbers in parentheses are the standard errors of the coefficients.

D Gcalc = -0.07(± 0.12) + 1.04(± 0.08)D Gexp (6)

n = 3301 r = 0.991 s = 1.12 F = 175000

In spite of these excellent correlations, we noted in [6] that the free energy values of a number of strong H-bond complexes involving nitrogen atoms deviated significantly from those calculated by equation (6).

Some of the obstacles in determining the relative strengths of H-bond donors and acceptors by the thermodynamic approach are: (i) in compounds with multiple polar atoms, identifying those atoms directly participating in H-bond formation, (ii) the difficulty of evaluating weak acceptor centres located near strong ones, (iii) the difficulty of determining the acceptor strengths of compounds with charged groups, and (iv) compounds with poor solubility in nonpolar solvents.

Factor calculations based on experimental log P values

Testa and coworkers [10,11] demonstrated that the distribution coefficient of a solute between octanol and water encodes two main structural contributions: the molecular volume of the solute, and the polar interactions between the solute and the solvent. They showed that the latter appears to consist mainly of the H-bond acceptor capacity of the solute. This was the starting point for a new approach to overcome some of the problems [(i)-(iv)] indicated above.

For this purpose, we elected to study a set of simple organic compounds each containing just one acceptor group. Experimental log P values (octanol-water) were taken from the literature. We used polarizabilities (Pol) as estimates for volumes; the computations were based on a literature method [12]. Free energy acceptor factors, Ca(t), were calculated by the method described in the previous section. The results are summarized in the following equation:

log P = 0.266(± 0.006)Pol - 1.00(± 0.05)Ca(t) (7)

n = 71 r = 0.991 s = 0.18 F = 3829

The excellent statistical results expressed in equation (7) afford an opportunity to estimate log P on the basis of computed values for Pol and Ca(t). The intercept for equation (7) is essentially zero; hence, rearrangement of the terms in equation (7) and substitution of Ca(o) for Ca(t) leads to equation (8). This enables the construction of a new scale of factors.

Ca(o) = 0.266Pol - log P (8)

Ca(t) indicates that the H-bond acceptor factor value is based on the thermodynamic database; Ca(o) indicates that the factor stems from log P (either measured or calculated) and calculated Pol; both pieces of information are readily available. For simple substances containing only one acceptor group, Ca(t) and Ca(o) will be approximate in value. In the case of complex organic compounds, the factor value will be the sum of factor values for each acceptor site in the molecule [S Ca(o)].

Factor calculations based on chemical structures

A HYBOT module is used to determine both donor and acceptor factor values for new molecules, even those with many H-bond centres. The structure of the molecule of interest is explored to find fragments corresponding to known compounds in the H-bond Factor libraries. If a good match is found then the database factor value for that match is used for that portion of subject molecule. If a structural fragment is not found in the database then HYBOT calculates it. An account of the method used to evaluate chemical structural environments has been published [8].

Examples of successful Application H-bond Descriptors

I. Solubility in water [unpublished data]

log(1/S) = - 0.42(± 0.20) + 0.17(± 0.11)Pol - 0.13(± 0.04)S Ca + 0.08(± 0.06)S Cd

n = 45 r = 0.925 s = 0.42

where Pol is polarizability, S Ca is the sum of all acceptor factor values and S Cd is the sum of all donor factor values.

II. LogP (octanol-water) [29]

log P = 0.266(± 0.005)Pol - 1.00 (± 0.03)Ca

n = 2781 r = 0.971 s =0.32

III. Permeability

1. Caco-2 Permeability (logPerm ) [30]

logPerm = 0.05(± 0.01)MW - 0.20(± 0.03)S Cad

n = 17 r = 0.883

where S Cad is the sum of absolute Ca and Cd values for all H-bond donor and acceptor atoms in molecule, and MW is molecular weight.

2. Human skin permeability (logKp) of steroid hormones [30]

logKp = - 4.36(± 0.61) - 0.38(± 0.09)Ca + 0.24(± 0.11)Cd

n = 14 r = 0.961 s = 0.30

3. Human skin permeability (logKp) of phenols [30]

logKp = -3.39(± 0.59) + 0.71(± 0.21)Cd

n = 17 r = 0.883 s = 0.28

4. Human skin permeability (logKp) of 23 diverse compounds [30]

logKp = - 2.12(± 0.11) - 0.41(± 0.02)S Ca(t) + 0.40(± 0.04)log P

n = 23 r = 0.977 s = 0.28

5. Human Red Cell Basal Permeability (log BP) of alcohols, water, urea and thiourea [30]

log BP = -0.70(± 0.64) + 1.08(± 0.16)Cd

n = 10 r = 0.983 s = 0.43

6. Permeability (logPerm) of nonelectrolytes through the cells of the alga Chara ceratophylla [30]

log Perm = 0.83(± 0.57) + 0.59(± 0.12)Cd

n = 27 r = 0.903 s = 0.49

7. Placental Transfer ratio (logTR) of drugs [30]

logTR = 0.28(± 0.18) - 0.05(± 0.02)Ca + 0.04(± 0.02)Cd

n = 16 r = 0.910 s = 0.13

IV. Absorption and bioavailability

1. Absorption and intraduodenal bioavailability (log AUCid ) of azole endothelin antagonists [30]

logAUCid = -4.318(± 1.048) + 0.408(± 0.138)Cd

n = 9 r = 0.935 s = 0.319

V. Biological activities

1. Tadpole narcosis [log(1/C]) [9]

log(1/C) = 0.49(± 0.20) + 0.23(± 0.02)Pol - 0.42(± 0.05)Ca

n = 85 r = 0.954 s = 0.33

2. Affinities for muscarinic receptor (logKi) by some bicyclic compounds [27]

logKi = - 4.58(± 0.48) - 0.09(± 0.06)Ca + 1.08(± 0.15)logP + 0.27(± 0.08)HBA5.3Å

n = 27 r = 0.918 s = 0.38

where HBA5.3Å = intensity of interaction of H-bond acceptors at a distance of 5.3 Å

3. Anti-HIV-1 activity (logKi)of porphyrines [9]

logKi = - 6.56(± 1.44) - 2.24(± 0.11)LUMO + 0.05(± 0.03)HBD11.4Å

n = 13 r = 0.961 s = 0.22

where HBD11.4 Å = intensity of interaction of H-bond donors at a distance of 11.4 Å.

4. Symmetrical cyclicurea HIV protease inhibitors [28]

-log Ki = 11.55(± 1.80) + 0.10(± 0.02)CLOGP2 - 0.95(± 0.26)CLOGP - 0.78(± 0.31)mv
- 0.008(± 0.002)MW - 0.48(± 0.12)Cd(t)NH + 0.51(± 0.09)Ca(t)N

n = 30 r = 0.895 s = 0.33

where log Ki is the inhibition constant; CLOGP is the calculated log P (MedChem program, Pomona College); mv is 1/100th the molecular volume; Cd(t)NH is the H-bond donating factor for a specific amide function; and Ca(t)N is the H-bond acceptor factor for a specific heteroaromatic nitrogen atom.

5. Anticonvalsive activity (log1/C0) of macrocyclic compounds [31]

log(1/C0) = 5.12(± 1.11) - 29.9(± 0.64)Ca - 0.20(± 0.14)HBA3.6 Å
+ 0.19(± 0.03)HBA5.3 Å

n = 16 r = 0.908 s = 0.20

where HBA3.6 Å = intensity of interaction of H-bond acceptors at a distance of 3.6 Å, and HBA5.3 Å = intensity of interaction of H-bond acceptors at a distance of 5.3 Å

Literature

  1. Sherry, A. D.; Purcell, K. F. Linear Enthalpy-Spectral Shift Correlations for 2,2,2-Trifluoroethanol. J.Phys.Chem. 1970, 74, 3535-3543.
  2. Iogansen, A. V. The Rule of Product of Function for Acids and Bases in Hydrogen Bonding in Tetrachloromethane. Teor. Eksperim. Khim. (Rus.), 1971, 7, 302-311.
  3. Raevsky, O. A.; Novikov, V. Classification of Donor-Acceptor Interaction Parameters in Framework of QSAR. Khim.-Pharm. Zhurn. (Rus.) 1982, 16, 583-586.
  4. Raevsky, O. A.; Avidon, V. V.; Novikov, V. The Application of Common Scale of Donor-Acceptor Interaction in QSAR. Khim.-Pharm. Zhurn. (Rus.), 1982, 16, 968-971.
  5. Raevsky, O. A.; Grigor'ev, V. Yu.; Solov'ev, V. P. The Estimation of Donor-Acceptor Parameters in Biologically Active Compounds. Khim.-Pharm. Zhurn. (Rus.) 1989, 23, 1294-1300.
  6. Raevsky, O. A.; Grigor'ev, V. Yu.; Kireev, D. B.; Zefirov, N. S. Complete Thermodynamic Description of H-Bonding in the Framework of Multiplicative Approach. Quant. Struct.-Act. Relat. 1992, 11, 49-63.
  7. Abraham, M. H.; Grellier, P. L.; Prior P. L.; et al. A General Treatment of Hydrogen Bond Complexation Constants in Tetrachloromethane. J. Am. Chem. Soc. 1988, 110, 8534-8536.
  8. Trepalin, S. V.; Yarkov, A. V.; Dolmatova, L. M.; Zefirov, N. S.; Finch, S. A. E. WinDat: An NMR Database Compilation Tool, User Interface, and Spectrum Libraries for Personal Computers. J. Chem. Inf. Comput. Sci. 1995, 35, 405-411.
  9. Raevsky, O. A. Quantification of Non-covalent Interactions on the Basis of the Thermodynamic Hydrogen Bond Parameters. J. Phys. Org. Chem. 1997, 10, 405-413.
  10. Van de Waterbeemd, H.; Testa, B. Adv. Drug Res. 1987, 16, 87-227.
  11. Tayar, N. E.; Testa, B. Polar Intermolecular Interactions Encoded in Partition Coefficients and Their Interest in QSAR. In Trends in QSAR and Molecular Modelling 92, Ed., Wermuth, C. G., ESCOM, Leiden, 1993, pp. 101-108.
  12. Miller, K. J. Additivity Methods in Molecular Polarizability. J. Am. Chem. Soc. 1990, 112, 8533-8542.
  13. Raevsky, O. A.; Grigor’ev ,V. Yu.; Kireev, D. B.; Zefirov, N. S. Correlation Analysis and H-bond Ability in Framework of QSAR. J. Chim. Phys. 1992, 89, 1747-1753.
  14. Schneider, H.-J.; Blatter, T.; Eliseev, A.; Rudiger, V.; Raevsky, O. A. Electrostatics in Molecular Recognition: from Ion Pairs and Ionophores to Nucleotides and DNA. Pure & Appl.Chem. 1993, 65, 2329-2334.
  15. Raevsky, O. A.; Grigor’ev, V. Yu.; Mednikova, E. QSAR H-Bonding Descriptors. In Trends in QSAR and Molecular Modelling; Wermuth, C. G., Ed.; Escom, Leiden: 1993, pp 116-119;
  16. Kireev, D. B.; Raevsky, O. A.; Fetisov, V. I. QSAR H-Bonding Descriptors., In Trends in QSAR and Molecular Modelling;. Wermuth, C. G., Ed; Escom, Leiden: 1993, pp 331-332.
  17. Raevsky, O. A.; Sapegin, A. M.; Zefirov, N. S. The QSAR Discriminant-Regression Model, Quant. Struct.-Act. Relat. 1994, 13, 412-418.
  18. Kireev, D. B.; Chretien, J. K.; Raevsky, O. A. Molecular Modelling and QSAR Studies of Anti-HIV of 1,2--heteroarylquinoline-4-amines. Eur. J. Med. Chem. 1995, 30, 395-402.
  19. Raevsky, O. A.; Schaper, K.-J.; Seydel, J. K. H-Bond Contribution to Octanol-Water Partition Coefficient of Polar Compounds. Quant. Struct.-Act. Relat. 1995, 14, 433-436.
  20. Raevsky, O.A. Quantitative Description of H-Bonding. Newsletter of QSAR Society 1995, Number 5, pp 2-5;
  21. Schneider, H.-J.; Rudiger, V.; Raevsky, O. A. The Incremental Description of Host-Guest Complexes: Free Energy Increments Derived from Hydrogen Bonds Applied to Crown Ethers and Cryptands. J. Org. Chem. 1993, 58, 3648-3653.
  22. Raevsky, O. A.; Dolmatova, L.; Grigor’ev, V.; Bondarev, S. Molecular Recognition Descriptors in QSAR. In QSAR and Molecular Modelling: Concepts, Computional Tools and Biological Applications; Sanz, F.; Giraldo, J., Eds.; Prous Science Publ., Barcelona: 1995, pp 241-245.
  23. Kitova, I. I.; Raevsky, O. A.; Blinova, V. G.; Zefirov, N.S. Statistical and Logico-Structural Approaches in QSAR Analysis of Anti-HIV Activity. ibid., pp 160-162.
  24. Razdolsky, A. N.; Lomova, O.; Sukhachev, D.; Tkachenko, S.; Raevsky, O. A.; Zefirov, N. S. ibid., pp 661-662.
  25. Raevsky, O. A. Program Package HYBOT( HYdrogen Bond Thermodynamics). Newsletter of QSAR and Modelling Society, 1996, Number 7, p16.
  26. Van de Waterbeemd, H.; Gamenisch, G.; Folkers, G.; Raevsky, O.A. Estimation of Caco-2 Cell Permeability using Calculated Molecular Descriptors. Quant. Struct.-Act. Relat. 1996, 15, 480-490.
  27. Raevsky, O. A. Hydrogen Bond Strength Estimation by means of HYBOT. In Computer-Assisted Lead Finding and Optimization; van de Waterbeemd, H; Testa, B.; Folkers, G., Eds.; Verlag: Basel, 1997, pp. 367-378;
  28. Waterbeemd H., Camenisch G., Folkers G., Chretien J., Raevsky O., Estimation of Blood-Brain Barrier Crossing of Drugs Using Molecular Size and Shape, and H-Bonding Descriptors, Journal of Drug Targeting, 1998, v.6, pp. 151-165.
  29. Raevsky O.A., K.-J.Schaper, H.Waterbeemd, J.McFarland, Hydrogen Bond Contribution to Properties and Activities of Chemicals and Drugs, in Molecular Modeling and Prediction of Bioactivity, eds. K.Gundertofte and K.Jorgensen, Kluwer Academic/Plenum Publishers, N.J., 1999, pp. 221-228.
  30. McFarland, J. W.; Raevsky, O. A.; Wilkerson, W. W. Hydrogen Bond Acceptor and Donor Factors, Ca and Cd: New QSAR Descriptors. In Molecular Modelling and Prediction of Bioactivity, eds. K.Gundertofte and K.Jorgensen, Kluwer Academic/Plenum Publishers, N.J., 1999, pp. 000.
  31. Raevsky, O. A.; Grigor'ev, V. Yu. Quantitative Description of Lipophilicity of Organic Compounds on the Basis Polarizability and Acceptor Ability to Formation of Hydrogen Bond. Khim.-Pharm. Zhurn. (Rus.) 1998, pp. 63-68.
  32. Raevsky, O. A.; Schaper, K. S. Quantitative Estimation of Hydrogen Bond Contribution to Permeability and Absorption Processes of Neutral Chemicals and Drugs. Europ. J. Med. Chem. 1998, v.33, pp.799-807.
  33. Lukoyanov, N. V.; Raevsky, O. A. Structure-anticonvulsant Activity Study in a Series of Macrocyclic Compounds. Voprosy Med. Khim. (Rus.) 1998, 44, 185-193.

Chapter 2 Technical Data

All data in HYBOT are contained in two databases: the Hydrogen Bond Thermodynamics Database and the Hydrogen Bonding Factors Database. Each database may to have several libraries. A library is a collection of entries (records) containing information about chemical compounds (the number of entries may be greater than number of chemical structures). Each structure has one or more H-bonding centres

Hydrogen Bond Thermodynamics Database:

Each entry has one hydrogen bonding complex, both acceptor and donor structures, and contains the thermodynamic properties, solvent, temperature and reference.

Number of libraries 1

Total number of entries 13,687

Hydrogen Bonding Factors Database:

Each entry has one chemical structure with the active centre marked, and contains donor factors values (those with a negative values) and/or acceptor factor values (those with a positive values).

Number of libraries 13

Total number of entries 67,710

Library

entries

Notes

ALPHA.CDB

363

a values calculated from D G

BETA.CDB

1613

b values calculated from D G

ALPH(CH).CDB

50

a values (CH-donors) calculated from D G

EA.CDB

1725

Ea factors calculated from D H

ED.CDB

164

Ed factors calculated from D H

ED(CH).CDB

44

Ed factors (CH-donors) calculated from D H

CA.CDB

1613

Ca factors calculated from D G

CD.CDB

363

Cd factors calculated from D G

CD(CH).CDB

50

Cd factors (CH-donors) calculated from D G

CA(O)

15293

Ca factors calculated from log P

CA(O)W

1665

Ca factors (week centres) calculated from log P

CA(O)NEW

42295

Ca factors calculated from log P (new)

CD_NEW

2472

Cd factors calculated from correlation data (new)

These libraries may be combined to form training sets for calculating factors for new chemical structures. Initially, HYBOT supplies some training sets that should be sufficient normal use. The following combinations make up these sets:

File

Combination

albeta.hbp

ALPHA + BETA

Hthermo.hbp

EA + ED

Gthermo.hbp

CA +CD

Gthermo2.hbp

CA + CD + CD_NEW

Overall.hbp

CA(O) + CD

Overall2.hbp

CA(O) + CD + CD_NEW

Overall3.hbp

CA(O) +CA(O)NEW + CD + CD_NEW

Chapter 3 MOLPRO: HBPlus Menu

The MOLPRO: HBPlus menu offers several options that are needed to calculate Ca, Cd, Ea, Ed, a and/or b factors for compounds. When you select the option MOLPRO: HBPlus in the Tools window you will see MOLPRO: HBPlus menu window:

The following table indicates what these options are and what they do.

MOLPRO: HBPlus option

Action

HBT database

Allows you to view/edit the hydrogen bond thermodynamics database.

HB Factor database

Allows you to view/edit the hydrogen bonding factor database.

HB factor calculation

Calculates the factors of a new molecule on the basis of experimental thermodynamic data.

Training set

Allows you to create a new training set made up of libraries of your choice. This option should be taken only by a user with sufficient knowledge of H-bonding and HYBOT to make judicious choices among the libraries. For most work one of the pre-formed training sets should be satisfactory.

Fragment definition

Allows you to enter and to edit factor values that can not be calculated from experimental data.

Descriptors: Libraries selection

Sets list of the files for calculation of the factors for many molecules (using a library).

Descriptors: Display

Allow you to see the results of calculation the descriptors for any molecule.

Descriptors: Calculate

Calculates the descriptors for a library.

Descriptors: Export to Excel

Exports the calculated descriptors into a spread sheet Microsoft ExcelTM

Descriptors: Export to Text file

Exports the calculated descriptors into a text file.

HB factors: Library selection

Sets list of the files for calculation of the factors for a single molecule and for many molecules (using *.sdf file).

HB factors: Element selection

Sets list of proton acceptors and proton donors for calculation of Ca, Cd, Ea, Ed, a and b factors.

HB factors: Predict

Calculates Ca, Cd, Ea, Ed, a and b factors for a single molecule on the basis of its chemical structure and an appropriate training set.

HB factors: Predict from file

Calculates Ca, Cd, Ea, Ed, a and b factors for many molecules on the basis of their chemical structures as described in the (*.sdf) file format (batch mode) and an appropriate training set.

HBT database

When you select this option you get the following Information window:

This window contains many data fields and buttons; the following table describes what they contain or do.

field name/button

information contained or action

ID

Shows the record number of the currently selected library entry.

® , ¬

From the current record in the list, the ® button takes you to the record next; the ¬ button takes you to the record prior.

Button: Update

When checked, allows you to edit data in the database.

+ , -

The + button allow to add new entry to database, the - button allow to delete selected entry.

Ö

The Ö button saves the selected entry.

Æ

The Æ button terminates the process without any action taken.

Zoom

Allow to change the size of the window.

Form

Selects a form for the database.

Table

Selects a table for the database.

-D G

Free energy of complex formation (kJ/mole).

-D H

Enthalpy of complex formation (kJ/mole).

Method G

Method of free energy determination.

Method H

Method of enthalpy determination.

 

Shift NMR

The difference in chemical shifts between free and associated H-bond donor groups (ppm).

Shift IR

The difference between the stretching frequencies for free and associated H bond donor groups (cm-1).

Type

Type of bridge in complex AH...B, where AH is the proton donor group, and B the proton acceptor atom.

Temperature

Temperature at which experiment was conducted in oK.

Solvent

Solvent used in the experimental determination.

Complex D/A

Stoichiometry of hydrogen bonding complex.

H-bond

Number of hydrogen bridges in H-bond complex.

Comment

Comments on the reference and data.

Authors

Authors of the reference publication.

Source

Name of journal or other reference from which the data were taken.

Year

Year of publication.

Volume

Journal volume.

Number

Journal number in particular volume.

Page

Pages of reference.

Molecular weight

Molecular weight of compound.

Name

Compound name.

CAS ID

Chemical Abstracts Registry Number.

Brutto formula

Brutto formula of compound.

Donor

Chemical structure of hydrogen bond donor.

Acceptor

Chemical structure of hydrogen bond acceptor.

HB Factor database

When you select this option you get the Open window. Select any *.cdb file and click. You see following Information window:

The following table explains what is contained in the data fields and what the buttons do.

field name/button

information contained or action

® , ¬

From the current record in the list, the ® button takes you to the record next; the ¬ button takes you to the record prior.

Button: Update

When checked, allows you to edit data in the database.

+ , -

The + button allow to add new entry to database, the - button allow to delete selected entry.

Ö

The Ö button saves the selected entry.

Æ

The Æ button terminates the process without any action taken.

Zoom

Allow to change the size of the window.

Form

Selects a form for the database.

Table

Selects a table for the database.

Structure

Structure of compound.

Name

Name of compound.

Brutto-formula

Brutto formula of compound.

Molecular weight

Molecular weight of compound.

CAS

CAS Registry Number.

C factor

The value of C-factor, E-factor or Alpha(beta)-factor.

To view active centre (coloured atom) click on Ca factor field. To view next structure use combination Ctrl + ¯ .

HB factor calculation

This option allows you to calculate hydrogen bonding factors (Ca, Cd, Ea, and Ed ) from the experimental hydrogen bond thermodynamics database for one centre in a molecule, and to add this information to a library in the factor database. This process is somewhat complicated, but if you

When you select option HB factor calculation in the MOLPRO: HBPlus menu you see the Factor Calculation window:

The following table explains the actions of the various items on the screen.

Item

Action

Save result in

Selects the name of the library to store newly calculated factors.

Field to save

Selects the field to store newly calculated factors.

Read data from

Selects the name of the library with the experimental data.

Search partners in

Selects the names of libraries with known factor values; select acceptor libraries when calculating donor factors, donor libraries when calculating acceptor factors.

Buttons: Calculate factors

Selects whether the new factors will be of the donor or the acceptor type.

Buttons: Kind of factors

Selects whether the new factors will be of the C or E type.

Add

Adds new library to list with known factors.

Delete

Deletes the library in the list with known factors.

OK

Calculates new factors from experimental data.

Cancel

Terminates the process without taking any action.

Training set

This option in the MOLPRO: HBPlus menu is used to create a new training set. If one of the pre-formed training sets serves your needs, then you probably should avoid using this option and simply select a training from those offered under the HB factors: Library selection or Descriptors: Libraries selection options. However, if you do select the option Training set you’ll see the Training Set window (any factor database will be active to afford data for training set).

The following table explains the actions of the various functions:

Item

Action

Filename

Selects the name of the file with training set.

Field to extract value and assignment

Selects the field, containing factors for training set.

Overwrite existing file

When checked, the new training set will be create, if not checked, then new data will be add to the old training set.

Start

Accepts selected options and begins the process.

Fragment definition

It is not possible to determine directly the H-bond acceptor strength of weak acceptors situated near strong ones. An important example is the nitrogen atom of an amide group. It is known in that the nitrogen acceptor factor value will be small compared to that of the cabonyl oxygen. Without a correction for this effect, the usual estimation in HYBOT will result values too large. However, there is an indirect way to estimate the H-bond factor value of such a weak acceptor: use the difference between the acceptor strength for the entire group of atoms (in the example, the amide group) and the acceptor strength of the dominant acceptor atom (in the example, the carbonyl oxygen). This principle was used to generate a set of 32 of structural fragments to accomodate this situation.

 

When you select option Fragment definition in the MOLPRO: HBPlus menu you will see the Fragment Definition window. Each fragment contains two colored atoms. The red atom represents the dominant acceptor atom; its value was calculated in the standard way on the basis of the H-bond Factor database. The green atom represents the weak acceptor atom; its value was estimated as described in the previous paragraph. The value K is the ratio of the factor value for the green atom to that of the red atom. When the box "Not use" in the Library Selection window is not checked (recommended), HYBOT will correct fragments with weak acceptors by multiplying the value normally obtained by the factor K.

The following table explains the actions of the various functions:

Item

Action

Fragment file

Selects the file with structural fragments.

Record

Shows the record number of the currently selected fragment entry.

t ,u

From the current record in the list, the t button takes you to the record above; the u button takes you to the record below.

K

Coefficient = Factor of green atom/Factor of red atom.

New record

Creates a new fragment.

Delete record

Deletes a selected fragment (under normal circumstances not recommended for any of the original 32 fragments).

Edit structure

Edits a selected fragment (under normal circumstances not recommended for any of the original 32 fragments).

Descriptors: Libraries selection

Use this option in the MOLPRO: HBPlus menu to select list of the work files to calculate factor values for many compounds in the library based on its chemical structure and an appropriate training set. . When you select this option the Library Selection window appears:

The following table explains the actions of the various items on the screen.

Item

Action

Filename

Selects one of the pre-formed training sets.

Fragments file

Selects the file with structural fragments.

Not use

When not checked (recommended), the calculation of the factors will include factors from fragments.

Libraries

Sets list of libraries to scan for exact structure matching.

Not use

When not checked (recommended), the calculation of the factors will include scan of the libraries.

Add library

Adds new library to list with libraries to scan.

Delete library

Deletes the library in the list with libraries to scan.

OK

Accepts selected options and jumps to the Start window.

Cancel

Terminates the process with no action being taken and jumps to the Start window.

Descriptors: Calculate

Use this option in the MOLPRO: HBPlus menu to calculate the descriptors on the basis factor values for many compounds in the library based on its chemical structure and an appropriate training set. . When you select this option the Calculate window appears (any library, containing the structures and the fields to store the calculated descriptors will be active).

The following table explains the actions of the various items on the screen.

Item

Action

Descriptors

Selects the list of descriptors to calculate.

Fields to save

Selects the fields in the library to store the calculated descriptors.

Calculate

Accepts selected options and calculates the descriptors.

Cancel

Terminates the process with no action being taken and jumps to the Start window.

Descriptors provided by HYBOT:

symbol

property

Comment

Alpha

molecular polarizability

sum of atomic polarizabilities; a measure of molecular volume

max(Ca)

largest Ca factor value

atom with greatest H-bond acceptor strength

max(Cd)

largest Cd factor value

atom with greatest H-bond donor strength

max(Q+)

most positive partial atomic charge

  

max(Q-)

most negative partial atomic charge

  

Sum(Ca)

total of Ca factor values

  

Sum(Cd)

total of Cd factor values

  

Sum(Q+)

total of positive partial atomic charges

  

Sum(Q-)

total of negative partial atomic charges

  

Sum(Abs(Q))

total of absolute partial atomic charges

  

SumC

sum of absolute C factor values

sign of factor values ignored

Sum(Q+)/Alpha

total of positive partial atomic charge/Alpha

positive partial atomic charge per unit of molecular volume

Sum(Q-)/Alpha

total of negative partial atomic charge/Alpha

negative partial atomic charge per unit of molecular volume

Sum(Ca)/Alpha

total of Ca factor values/Alpha

Ca factor value per unit of molecular volume

Sum(Cd)/Alpha

total of Cd factor values/Alpha

Cd factor value per unit of molecular volume

Sum(C)/Alpha

sum of absolute C factor values/Alpha

C factor values per unit of molecular volume

Descriptors: Display

To view the results of descriptor calculation for any compound select option Descriptors: Display in the MOLPRO: HBPlus menu and you will see the Display window (a library, containing the calculated descriptors will be active).

The following table explains the actions of the various items on the screen.

Item

Action

New

Allows you to calculate the descriptors for new molecule.

Print

Opens the Print Preview window. This display shows all the data in the Display window as it will be printed. To print this screen click on the Print button. If you don’t want to print this screen, click on Close button to return to the Display window.

Descriptors: Export to Excel

You can export the calculated descriptors in a spreadsheet Microsoft Excel™. When you select option Descriptors: Export to Excel the Export window appears (a library, containing the calculated descriptors will be active).

The following table explains the actions of the various functions:

Item

Action

Fields to be exported

Selects the descriptors to export.

­ , ¯

The current record in the list, the ­ button move above; the ¯ button move below.

Start

Accepts selected options and begins the process.

Descriptors: Export to Text file

You can export the calculated descriptors in a text file. When you select option Descriptors: Export to Text file the Save as window appears (a library, containing the calculated descriptors will be active).

Type name of the text file and click Save. The Export window appears (see Descriptors: Export to Excel).

HB factors: Library selection

Use this option in the MOLPRO: HBPlus menu to select list of the work files to calculate factor values for a single compound or for many compounds in batch mode based on its chemical structure and an appropriate training set. . When you select this option the Library Selection window appears:

The following table explains the actions of the various items on the screen.

Item

Action

Filename

Selects one of the pre-formed training sets.

Fragments file

Selects the file with structural fragments.

Not use

When not checked (recommended), the calculation of the factors will include factors from fragments.

Libraries

Sets list of libraries to scan for exact structure matching.

Not use

When not checked (recommended), the calculation of the factors will include scan of the libraries.

Add library

Adds new library to list with libraries to scan.

Delete library

Deletes the library in the list with libraries to scan.

OK

Accepts selected options and jumps to the Start window.

Cancel

Terminates the process with no action being taken and jumps to the Start window.

HB factors: Element selection

As is known, that as proton donors act usually the groups OH, NH, SH, ( less often CH ), and as proton acceptors the atoms O, N, S ( less often F, Cl, Br, I, Pi-systems ). By default (empty list of elements) the factors are calculated for all elements. At inclusion of any element in the list will be calculated the factors only for this element.

When you select option HB factors: Element selection in the MOLPRO: HBPlus menu you will see the Elements Definition window.

The following table explains the actions of the various items on the screen.

Item

Action

List of elements to be predicted

Sets list of proton acceptors and proton donors for calculation of Ca, Cd, Ea, Ed, a and b factors.

Delete

Deletes the atom in the list with proton acceptors and proton donors.

OK

Accepts selected options and jumps to the Start window.

Cancel

Terminates the process with no action being taken and jumps to the Start window.

HB factors: Predict

Use this option in the MOLPRO: HBPlus menu to calculate factor values for a single compound based on its chemical structure and an appropriate training set. When you select this option the Structure Editor window appears:

Draw the chemical structure of the compound in which you are interested; then select option OK. HYBOT jumps to the Result window and shows the structure drawn with the relevant factor information in tabular form.

At this point only one marked atom is shown. To see the others click: i) on each atom what you want ii) on any line in the table.

HB factors: Predict from file

This option allows you to estimate factors for many compounds in batch mode based on chemical structure alone from the factors database. For example, you may be interested in hydrogen bonding factors for a series of compounds found in an ISISTM database. A selection of compounds from this database can be saved in *.sdf file format. Such a file can supply the chemical structural information to HYBOT so that it can then make the calculations on the entire group of compounds. In this mode, the information output is placed in a comma delimited text file that can then be imported into a spread sheet such as Microsoft ExcelTM for viewing and/or further manipulation.

When you select the option Predict from file in the MOLPRO: HBPlus menu you jump to an Open File window. You must choose the desired *.sdf file.

You can move through the directories to locate that file; once it is found click on it to select it, and then click on Open. HYBOT proceeds to calculate the hydrogen bonding factors. When finished it will place the results in a comma delimited text file in the same directory from which the *.sdf file was taken. The name of the file is pred.dat.

Chapter 4 Learning HYBOT

In the following tutorials it is assumed that you know how to perform basic operations with your computer: starting applications from Microsoft Windows, sizing, moving and scrolling through windows, opening menus and choosing menu items. In the following scenarios, click means that you should select an item by pressing the left mouse button; R-click means that you should select an item by pressing the right mouse button.

Searching Entries

Suppose you want to find in the hydrogen bond thermodynamics database all entries that match the following criteria: hydrogen bond acceptors with amide fragments, tetrachloromethane as the solvent, and the free energy of complexation in the interval from -14 kJ/mole to -13 kJ/mole.

To select entries:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the HBT database item. The Information window opens.
  4. Click on Search in the Start window. A dialog box appears.
  5. Click on the Find item. The Search window opens.
  6. Position the mouse pointer on Acceptor in the Database(s) searchable fields list and click.
  7. Position the mouse pointer on Fragment in the Search type list and click.
  8. Double click on Structure in the Search window. The Structure Editor window opens.
  9. Click on the Templates button. The new items appear.
  10. Click on Groups item. A window with various chemical group structures opens.
  11. Click on amide fragment H2N - C=O. The Structure Editor window reappears.
  12. Position the mouse pointer on centre of the screen and click. You will see amide group.
  13. Click on OK. The Search window opens.
  14. Click on Execute and the search begins. All entries found are marked. There are 1508 entries.
  15. Position the mouse pointer on Solvent in the Database(s) searchable fields list and click. The Solvent dialog box appears.
  16. Click on Solvent in the Search window. The Solvent dialog box appears.
  17. Select CCl4 from the list.
  18. Position the mouse pointer on Compress no. found records in the Search continuation list and click.
  19. Click on Execute. Of the original 1508 compounds 961 results were obtained where CCl4 was the solvent used in the determination.
  20. Position the mouse pointer on G in the Database(s) searchable fields list and click. The Numerical window appears.
  1. Click on the Minimal value box in Numerical window and type 13.0, click on Maximal value box and type 14.0.
  2. Click on Execute. Only 54 entries match all of the selection criteria.
  3. Close Search window. The Information window for the Hydrogen bond thermodynamics database then opens. All entries found are marked.

To view entries

You can view the results by scrolling through the list; click on the marked arrows to see the list of compounds matching the selection criteria.

Adding Entries

Let us say that you want to add a new entry to the hydrogen bonding thermodynamics database. The following data need to be entered: the hydrogen bond donor, 3,5-difluoro-4-chlorophenol; the hydrogen bond acceptor, pyridine; the solvent tetrachloromethane; the free energy of complexation, -13 kJ/mole; the enthalpy of complexation, -20 kJ/mole; the complex, 1:1, the experimental method, infrared spectroscopy; the temperature, 298 K; one hydrogen bond between OH group of H-donor and nitrogen atom of H-acceptor; author, Smith A.; the literature source, Journal of Molecular Structure, 1995, Vol. 50, pp. 100-106. You may add a new entry in an existing library or create of a new library. For example, you want to add the new entry in existing library HBTHERMO.

To add a new entry:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the HBT database item. The Information window for the H-bond data base opens.
  4. Turn on button Update in the Information window.
  5. Click on + button. The Information window is clear.
  6. Position the mouse pointer in the -D G window and type 13.0.
  7. Position the mouse pointer in the -D H window and type 20.0.
  8. Double click on Method G). The Method dialog box appears.
  9. Select IR item and click.
  10. Double click on Method H. The Method dialog box appears.
  11. Select IR item and click.
  12. Position the mouse pointer on H-bond window and type 1.
  13. Double click on Type. The Type dialog box appears.
  14. Select the OH...N item and click.
  15. Position the mouse pointer on Temperature window and type 298.
  16. Position the mouse pointer on Complex D/A window and type 1:1.
  17. Double click on Solvent. The Solvent dialog box appears.
  18. Select CCl4 item and click.
  19. Position the mouse pointer on Authors window and type Smith A.
  20. Double click on Source. The Source dialog box appears.
  21. From the list select J. Mol. Struct. and click.
  22. Position the mouse pointer on Year window and type 1995.
  23. Position the mouse pointer on Volume window and type 50.
  24. Position the mouse pointer on Page window and type 100-106.
  25. Position the mouse pointer on Name H-bond donor window and type 3,5-difluoro-4-chlorophenol.
  26. Position the mouse pointer on Name H-bond acceptor window and type pyridine.
  27. Position the mouse pointer on Donor window and double click. The Structure Editor window opens.
  28. Click on Templates button. The new items appear.
  29. Click on Ring item. Various chemical structural templates appear in a window.
  30. Click on the benzene ring. The Structure Editor window reappears.
  31. Position the mouse pointer on the centre of the screen and click. You will see a benzene ring.
  32. Click on Atoms button. The new items appear.
  33. Click on the O item; then click on a C atom in benzene ring. You will see phenol.
  34. Click on the F item, then click on the 3- and 5- C atom positions in the benzene ring. You will see 3,5-difluorophenol.
  35. Click on the Cl item; then click on the 4-C atom position in the benzene ring. You will see 3,5-difluoro-4-chlorophenol.
  36. Click on OK item. The Information window reappears.
  37. Position the mouse pointer on Acceptor window, and double click. The Structure Editor window opens.
  38. Click on Templates button. The new items appear.
  39. Click on Ring item. Various chemical structural templates appear in a window.
  40. Click on the benzene ring. The Structure Editor window reappears.
  41. Position the mouse pointer on the centre of the screen and click. You will see a benzene ring.
  42. Click on Atoms button. The new items appear.
  43. Click on the N item, then R-click on a C atom in benzene ring. You will see pyridine.
  44. Click on OK item. The Information window reappears.
  45. Click on Ö button in the Information window. You will now have the new entry in the library HBTHERMO.

Calculation Factors from Experimental Data

(Please don't use this procedure without special need. The calculated factor values loaded in the factor data bases of your copy of HYBOT-PLUS-2000/CHED were prepared by our specialists with long time experience in the field.)

This method is used to calculate the hydrogen bonding factors (Ca, Cd, Ea, Ed, a ,b ) for one centre in a molecule (one centre model).

Suppose you want to calculate the proton donor free energy (Cd) factors of the hydrogen bond donors. You must have a library (for example HBTHERMO, see previous exercise) in the hydrogen bond thermodynamics database with one or more entries including the structures of H-bond donors and an H-bond acceptors, the values of the free energy and enthalpy, the solvent and the temperature (see previous exercise). You can add a new factor to an existing library in Hydrogen bonding factors database or create of a new library. For example, you may want to add the new factors to a new library, FNEW. Also you must have library with known proton acceptor free energy (Ca) factors, the library CA will do.

To create a new library FNEW:

  1. Click on File in the Start window. A dialog box appears.
  2. Click on New item. A dialog box appears.
  3. Type FNEW (library name), click on Open. The Database content window appears.
  4. Click on Append item. The Database field definition window appears.
  5. Position the mouse pointer on Field name window and type, for example, Cd.
  6. Position the mouse pointer on Type window and select Real.
  7. Click on OK. The Database content window appears.
  8. Click on OK. The Information window appears.
  9. Click on View in the Start window. A dialog box appears.
  10. Click on Edit form item. The Form edition window appears. You see Structure, Molecular weight and Brutto-formula forms.
  11. Position the mouse pointer on free place (any point), click and drug. The Cd form appears.
  12. Click on OK. The Start/Information windows appear.
  13. The Factors database now contains a new library named FNEW.

To calculate new factors from experimental data:

  1. Click on Tools/MOLPRO: HBPlus/HB factor calculation item in the Start window. The Libraries selection window opens.
  2. Click on Save result in item. A dialog box appears.
  3. Select FNEW (library name), click on Open. The Information window appears.
  4. Position the mouse pointer on Libraries selection item (bottom of the screen) and click. The Libraries selection window appears.
  5. Click on Read data from item. A dialog box appears.
  6. Select HBTHERMO (library name), check the content of the windows named Donor structure, Acceptor structure, Solvent field, Delta G and Temperature. If it is necessary change their contents using a key from the right and click on OK. The Libraries selection window appears.
  7. Click on Add item. A dialog box appears.
  8. Select CA (library name), click on Open. The Information window appears.
  9. Position the mouse pointer on Libraries selection item (bottom of the screen) and click. The Libraries selection window appears.
  10. Position the mouse pointer on Donor item in the Calculate factors list and click.
  11. Position the mouse pointer on C item in the Kind of factors list and click.
  12. Click on OK. The process takes some time.
  13. The library FNEW has a new entries containing the proton donor free energy (Cd) factors.

Prediction of Factors for a Single Chemical Structure

This method is used to calculate factors (a , b , Cd, Ca, Ed and Ea) for many centres in a molecule (many centres model).

For example, you want to calculate the C-factors of 3-methoxyphenol by using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to scans the content of libraries CA(O), CD, CD_NEW in Hydrogen bonding factors database and, if the exact structure is not found, to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).

Scan the libraries that are the same as training set.

(RECOMMENDED TRAINING SET IS Overall2.hbp)

To predict new factors from chemical structure:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the Library selection item. The Library selection window opens.
  4. Click on Filename button. A dialog box appears.
  5. Select Overall2.hbp file, click on Open. The Library selection window appears.
  6. Click on Fragments file button. A dialog box appears.
  7. Select hbfrag.sfg file, click on Open. The Library selection window appears.
  8. Click on Add library button. A dialog box appears.
  9. Select CA(O).cdb, click on Open. The Library selection window appears.
  10. Click on Add library button. A dialog box appears.
  11. Select CD.cdb, click on Open. The Library selection window appears.
  12. Click on Add library button. A dialog box appears.
  13. Select CD_NEW.cdb, click on Open. The Library selection window appears.
  14. Clear radio button Not use.
  15. Click on OK. The Start/Information window appear.
  16. Click on Tools in the Start window. A dialog box appears.
  17. Click on the MOLPRO: HBPlus item. A dialog box appears.
  18. Click on the Predict item. The Structure Editor window opens.
  19. Click on Templates button. The new items appear.
  20. Click on Ring item. Various chemical structural templates appear in a window.
  21. Click on the benzene ring. The Structure Editor window reappears.
  22. Position the mouse pointer on centre of the screen and click. You will see benzene.
  23. Click on Atoms button. The new items appear.
  24. Click on the O item; then click on a C atom in benzene ring; then click again on the C atom at position 3. You will see 3-hydroxyphenol.
  25. Click on the C item, then click on an O atom (3-position) in benzene ring. You will see 3-methoxyphenol.
  26. Click on the H item, then click on the phenolic O atom (1-position) in benzene ring. You will see 3-methoxyphenol with the H donor bond shown.
  27. Click on OK. A Result window appears.

To view results of predicting of new factors:

  • You will see the chemical structure (picture) and predicted factors (table). To see the factor value for any atom click on them (picture) or mark any line (table).

Prediction Factors for File of Chemical Structures (batch mode)

Use this method to calculate the factors (a , b , Cd, Ca, Ed and Ea) for many multicentred` compounds from an *.sdf file of chemical structures. The output will be a comma delimited text file that can be imported into a spreadsheet such as Excel™. From this spreadsheet you can manipulate the data further and/or view the results.

Suppose you want to calculate the C-factors for a series of compounds from a file in which the structures are in the *.sdf format (you must create this file from a chemical database, for example ISIS/Base™), using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to scans the content of libraries CA(O), CD, CD_NEW in Hydrogen bonding factors database and, if the exact structure is not found, to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).

Scan the libraries that are the same as training set.

(RECOMMENDED TRAINING SET IS Overall2.hbp)

To predict new factors for a series of chemical structures:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the Library selection item. The Library selection window opens.
  4. Click on Filename button. A dialog box appears.
  5. Select Overall2.hbp file, click on Open. The Library selection window appears.
  6. Click on Fragments file button. A dialog box appears.
  7. Select hbfrag.sfg file, click on Open. The Library selection window appears.
  8. Click on Add library button. A dialog box appears.
  9. Select CA(O).cdb, click on Open. The Library selection window appears.
  10. Click on Add library button. A dialog box appears.
  11. Select CD.cdb, click on Open. The Library selection window appears.
  12. Click on Add library button. A dialog box appears.
  13. Select CD_NEW.cdb, click on Open. The Library selection window appears.
  14. Clear radio button Not use.
  15. Click on OK. The Start/Information window appear.
  16. Click on Tools in the Start window. A dialog box appears.
  17. Click on the MOLPRO: HBPlus item. A dialog box appears.
  18. Click on the Predict from file item. The dialog box appears.
  19. Look through the directories to find the *.sdf file you want. When you have found it, select it and then click on Open. The process takes some time. The Start window appears.

To view results of predicting new factors:

In the same directory from which you took the *.sdf file, find a new ASCII comma delimited text file with the name pred.dat. The output format is: compound identifiers, factor values, and atom type/location, e.g. N23, a nitrogen atom acceptor found in position 23 of the molecule or HO16, a hydrogen bond donor found on the oxygen atom at 16 position of the molecule. Some times the compound identifiers are not picked up in this operation; in this case the first entry of each row will start with a comma, ’’,’’. It is advisable to import this file into a spreadsheet; some manipulation of the data may be required to make them understandable.

Prediction of Factors and Calculation Descriptors for Library of Chemical Structures

Use this method to calculate the descriptors on the basis factor values for many multicentred` compounds from an library of chemical structures.

Suppose you want to calculate all descriptors for a series of compounds from a new library DRUGS, using an import of any *.sdf file and using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).

(RECOMMENDED TRAINING SET IS Overall2.hbp)

To create a new library DRUGS and to import *.sdf file:

  1. Click on File in the Start window. A dialog box appears.
  2. Click on New item. A dialog box appears.
  3. Type DRUGS (library name), click on Open. The Database content window appears.
  4. Click on Append item. The Database field definition window appears.
  5. Position the mouse pointer on Field name window and type Alpha.
  6. Position the mouse pointer on Type window and select Real.
  7. Click on OK. The Database content window appears.
  8. Click on Append item. The Database field definition window appears.
  9. Position the mouse pointer on Field name window and type MaxCa.
  10. Position the mouse pointer on Type window and select Real.
  11. Click on OK. The Database content window appears.
  12. Click on Append item. The Database field definition window appears.
  13. Position the mouse pointer on Field name window and type MaxCd.
  14. Position the mouse pointer on Type window and select Real.
  15. Click on OK. The Database content window appears.
  16. Click on Append item. The Database field definition window appears.
  17. Position the mouse pointer on Field name window and type MaxQ+.
  18. Position the mouse pointer on Type window and select Real.
  19. Click on OK. The Database content window appears.
  20. Click on Append item. The Database field definition window appears.
  21. Position the mouse pointer on Field name window and type MaxQ-.
  22. the mouse pointer on Type window and select Real.
  23. Click on OK. The Database content window appears.
  24. Click on Append item. The Database field definition window appears.
  25. Position the mouse pointer on Field name window and type SumCa.
  26. Position the mouse pointer on Type window and select Real.
  27. Click on OK. The Database content window appears.
  28. Click on Append item. The Database field definition window appears.
  29. Position the mouse pointer on Field name window and type SumCd.
  30. Position the mouse pointer on Type window and select Real.
  31. Click on OK. The Database content window appears.
  32. Click on Append item. The Database field definition window appears.
  33. Position the mouse pointer on Field name window and type SumQ+.
  34. Position the mouse pointer on Type window and select Real.
  35. Click on OK. The Database content window appears.
  36. Click on Append item. The Database field definition window appears.
  37. Position the mouse pointer on Field name window and type SumQ-.
  38. Position the mouse pointer on Type window and select Real.
  39. Click on OK. The Database content window appears.
  40. Click on Append item. The Database field definition window appears.
  41. Position the mouse pointer on Field name window and type SumAbsQ.
  42. Position the mouse pointer on Type window and select Real.
  43. Click on OK. The Database content window appears.
  44. Click on Append item. The Database field definition window appears.
  45. Position the mouse pointer on Field name window and type SumC.
  46. Position the mouse pointer on Type window and select Real.
  47. Click on OK. The Database content window appears.
  48. Click on Append item. The Database field definition window appears.
  49. Position the mouse pointer on Field name window and type SumQ+/Alpha.
  50. Position the mouse pointer on Type window and select Real.
  51. Click on OK. The Database content window appears.
  52. Click on Append item. The Database field definition window appears.
  53. Position the mouse pointer on Field name window and type SumQ-/Alpha.
  54. Position the mouse pointer on Type window and select Real.
  55. Click on OK. The Database content window appears.
  56. Click on Append item. The Database field definition window appears.
  57. Position the mouse pointer on Field name window and type SumCa/Alpha.
  58. Position the mouse pointer on Type window and select Real.
  59. Click on OK. The Database content window appears.
  60. Click on Append item. The Database field definition window appears.
  61. Position the mouse pointer on Field name window and type SumCd/Alpha.
  62. Position the mouse pointer on Type window and select Real.
  63. Click on OK. The Database content window appears.
  64. Click on Append item. The Database field definition window appears.
  65. Position the mouse pointer on Field name window and type SumC/Alpha.
  66. Position the mouse pointer on Type window and select Real.
  67. Click on OK. The Database content window appears.
  68. Click on OK. The Start/Information window appears.
  69. Click on File in the Start window. A dialog box appears.
  70. Click on Import item. A dialog box appears.
  71. Look through the directories to find the *.sdf file you want. When you have found it, select it and then click on Open. The Database fields matching window appears.
  72. Click on OK. The process takes some time. The Start/Information window appears.

To calculate descriptors for a library of chemical structures:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the Descriptors: Libraries selection item. The Library selection window opens.
  4. Click on Filename button. A dialog box appears.
  5. Select Overall2.hbp file, click on Open. The Library selection window appears.
  6. Click on Fragments file button. A dialog box appears.
  7. Select hbfrag.sfg file, click on Open. The Library selection window appears.
  8. In the Libraries window (bottom of the screen) check radio button Not use.
  9. Click on OK. The Start/Information window appear.
  10. Click on Tools in the Start window. A dialog box appears.
  11. Click on the MOLPRO: HBPlus item. A dialog box appears.
  12. Click on the Descriptors: Calculate item. The dialog box appears.
  13. Click on left buttons (Descriptors) and drag a line to right buttons (Fields to save).
  14. Click on Calculate item. The process takes some time. The Start/Information window appears.

To view results of calculating descriptors:

  1. Click on Tools in the Start window. A dialog box appears.
  2. Click on the MOLPRO: HBPlus item. A dialog box appears.
  3. Click on the Descriptors: Display item. The Display window appears.
 

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