A new paradigm for pattern recognition of drugs

Abstract

A new paradigm is suggested for pattern recognition of drugs. The approach is based on the combined application of the 4D/3D quantitative structure-activity relationship (QSAR) algorithms BiS and ConGO. The first algorithm, BiS/MC (multiconformational), is used for the search for the conformers interacting with a receptor. The second algorithm, ConGO, has been suggested for the detailed study of the selected conformers' electron density and for the search for the electron structure fragments that determine the pharmacophore and antipharmacophore parts of the compounds. In this work we suggest using a new AlteQ method for the evaluation of the molecular electron density. AlteQ describes the experimental electron density (determined by low-temperature highly accurate X-ray analysis) much better than a number of quantum approaches. Herein this is shown using a comparison of the computed electron density with the results of highly accurate X-ray analysis. In the present study the desirability function is used for the first time for the analysis of the effects of the electron structure in the process of pattern recognition of active and inactive compounds. The suggested method for pattern recognition has been used for the investigation of various sets of compounds such as DNA-antimetabolites, fXa inhibitors, 5-HT(1A), and alpha(1)-AR receptors inhibitors. The pharmacophore and antipharmacophore fragments have been found in the electron structures of the compounds. It has been shown that the pattern recognition cross-validation quality for the datasets is unity.

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information

“…The descriptors available in OCHEM are grouped by the software name that contributes them: ADRIANA.Code [31], CDK descriptors [32], Chemaxon descriptors [33], Chirality codes [34–38], Dragon descriptors [39], E-State indices [40], ETM descriptors [41, 42], GSFrag molecular fragments [43], inductive descriptors [44], ISIDA molecular fragments [45], quantum chemical MOPAC 7.1 descriptors [46], MERA and MerSy descriptors [47–50], MolPrint 2D descriptors [51], ShapeSignatures [52] and logP and aqueous solubility calculated with ALOGPS program [24]. The descriptor selection screen is shown in Fig.…”

“…MERA descriptors (3D) are calculated using the non-parametrical 3D MERA algorithm and include (a) geometrical MERA descriptors (linear and quadratic geometry descriptors, descriptors related to molecular volume, proportions of a molecule, ratios of molecular sizes, quantitative characteristics of molecular symmetry, dissymmetry, chirality), (b) energy characteristics (inter- and intra-molecular Van der Waals and Coulomb energies; decomposition of intermolecular energies) and (c) physicochemical characteristics (probabilities of association, heat capacity, entropy, pKa) [47–50, 59]. …”

“…Additionally, the molecular chirality is quantitatively evaluated in agreement with the negative criterion of chirality (the absence of inversion-rotational axes in the molecular point group) [47–50, 59]. …”

Modeling complexes of substrates with cytochrome P450 2C9

“…This approach was analogous to that used with the BiS/MC algorithm [28,29], which was previously used successfully to find active conformers and determine their orientation in the cavity of an actual receptor during an analysis of the biological activity of p38 MAP kinase inhibitors [28], to elucidate the details of the mechanism of action of DNA-antimetabolites and dihydrofolate reductase inhibitors [29], and to investigate fXa, 5-HT 1A , and á 1 -AR inhibitors [30]. The CiS algorithm was also used successfully to construct model complexes of cytochrome P450 isoform 1A2 [31].…”

“…The square of the amplitude A m is a range of atomic coordinates m of the model receptor upon carrying out an iterative procedure of orienting the drugs in the model receptor [23,30]. This consideration enables the structure of the actual complex to be reproduced more accurately.…”