A Generally Applicable Computer Algorithm Based on the Group Additivity Method for the Calculation of Seven Molecular Descriptors: Heat of Combustion, LogPO/W, LogS, Refractivity, Polarizability, Toxicity and LogBB of Organic Compounds; Scope and Limits of Applicability.

Rudolf Naef

doi:10.3390/molecules201018279

Abstract

A generally applicable computer algorithm for the calculation of the seven molecular descriptors heat of combustion, logPoctanol/water, logS (water solubility), molar refractivity, molecular polarizability, aqueous toxicity (protozoan growth inhibition) and logBB (log (cblood/cbrain)) is presented. The method, an extendable form of the group-additivity method, is based on the complete break-down of the molecules into their constituting atoms and their immediate neighbourhood. The contribution of the resulting atom groups to the descriptor values is calculated using the Gauss-Seidel fitting method, based on experimental data gathered from literature. The plausibility of the method was tested for each descriptor by means of a k-fold cross-validation procedure demonstrating good to excellent predictive power for the former six descriptors and low reliability of logBB predictions. The goodness of fit (Q2) and the standard deviation of the 10-fold cross-validation calculation was >0.9999 and 25.2 kJ/mol, respectively, (based on N = 1965 test compounds) for the heat of combustion, 0.9451 and 0.51 (N = 2640) for logP, 0.8838 and 0.74 (N = 1419) for logS, 0.9987 and 0.74 (N = 4045) for the molar refractivity, 0.9897 and 0.77 (N = 308) for the molecular polarizability, 0.8404 and 0.42 (N = 810) for the toxicity and 0.4709 and 0.53 (N = 383) for logBB. The latter descriptor revealing a very low Q2 for the test molecules (R2 was 0.7068 and standard deviation 0.38 for N = 413 training molecules) is included as an example to show the limits of the group-additivity method. An eighth molecular descriptor, the heat of formation, was indirectly calculated from the heat of combustion data and correlated with published experimental heat of formation data with a correlation coefficient R2 of 0.9974 (N = 2031).

Highlights

The published methods for the calculation of a molecular descriptor, if based on a given set of experimental data for known molecules, usually cannot be generalized, be it that they are based on certain molecular fragment parameters such as bond energies [1,2,3], only applicable for thermodynamic properties, be it that they are founded on simple atom contribution methods [4], referring to the atoms’ properties themselves or on substituents [5], which are of limited viability
The most promising approach was described by Ghose and Crippen for the calculation of the logPO/W values [6,7], where the molecules are broken down into a set of up to 110 atom types, for which the hydrophobicity contribution was calculated from experimental data using the group-additivity model and least-squares technique
The general algorithm for the calculation of the mentioned molecular descriptors is founded on the principle of atom group contributions in analogy to the method described by Ghose and Crippen [6,7], extended in some cases by a few specific terms which will be outlined later on

Summary

Introduction

The published methods for the calculation of a molecular descriptor, if based on a given set of experimental data for known molecules, usually cannot be generalized, be it that they are based on certain molecular fragment parameters such as bond energies [1,2,3], only applicable for thermodynamic properties, be it that they are founded on simple atom contribution methods [4], referring to the atoms’ properties themselves or on substituents [5], which are of limited viability. The most promising approach was described by Ghose and Crippen for the calculation of the logPO/W values [6,7], where the molecules are broken down into a set of up to 110 atom types, for which the hydrophobicity contribution was calculated from experimental data using the group-additivity model and least-squares technique. Miller [9,10] applied the group additivity method for the calculation of the molecular polarizability using atomic hybrid components and atomic hybrid polarizabilites, an approach which differs from the present one in that the type of the neighbourhood atoms is ignored

Methods

Results

Conclusion