The use of molecular docking by enzyme hydrolase E.Coli (S.Aureus) in the study of the «structure-activity» relationship in a series of substituted amides and hydrazide of N-aroyl anthranilic acids

Andryukov K. V.
PhD (Pharmacy), Assistant Professor, Chair for Pharmaceutical Chemistry¹

Korkodinova L. M.
Doctor of Pharmacy, Professor, Head, Chair for Pharmaceutical Chemistry¹

1 - Perm State Pharmaceutical Academy, Perm, Russia

Corresponding Author: Andryukov Konstantin; e-mail: k_andrukov@mail.ru. Conflict of interest. None declared. Funding. The study had no sponsorship.

The article focuses on the use of molecular docking for the enzyme E. Coli hydrolase (S. Aureus) in the study of the "structure-activity" relationship in the series of substituted amides and hydrazides of N-aroyl anthranilic acids. For the construction of the structure-activity model, we used the results of molecular docking on the enzyme peptide deformylase (hydrolase) E.Coli and S.Aureus of substituted amides and hydrazides of N-aroyl anthranilic acids. During the docking, E. Coli hydrolase enzymes (PDB ID code: 1LRU) and S. Aureus (PDB ID code: 1Q1Y) were used, the structures of which were obtained from the RCSB Protein Data Bank database. Before carrying out molecular docking, optimization and quantum-chemical calculation of the structures of the studied compounds was performed using the PM3 semiempirical method applying Gaussian 03 software. Significant parameters were determined: total electric field strength Σ (Е), potential Σ (φ) and the absolute value of charge Σ (|q|) on the atoms of oxygen, nitrogen, carbon and hydrogen. We carried out theoretical calculation of the physicochemical descriptors of the compounds under study: lipophilic constants (log P_calc), acidity constants (pKa_calc) and basicity (pKв_calc). Ligand-receptor interaction modeling was performed by the AutoDock 4.0 software as part of the MGL Tools 1.5.6 software package, using the Lamarkian genetic algorithm. As a result of docking for enzymes hydrolase E.Coli and S.Aureus, scoring functions were obtained: binding energy (Binding energy (Be_E.Coli and Be_S.Aureus)), intermolecular energy (Intermolecular energy (Ime_E.Coli and Ime_S.Aureus)) and inhibition constant (Ki_E.Coli and Ki_S.Aureus) characterizing the interaction of the ligand with the receptor. Studies of the dependence of antimicrobial activity (AA) from scoring functions and physicochemical descriptors were carried out. Structure-activity models were compiled by conducting multiple linear regression analysis using the Statistica 6 program. Four correlation equations were compiled relating the scoring functions and physico-chemical descriptors with antimicrobial activity using 20 compounds. A check was performed for the models created using the example of 4 compounds. Linear dependences of AA_calc. from experimental values of AA_exp. (MIC_exp.(E.Coli) and MIC_{exp.(S.Aureus)} for equations 2 and 4, made up of four, with correlation coefficients (R_pred. (2) = 0.961 and R_pred. (4) = 0.911), show a high degree of communication AA_calc. with AA_exp..

amide, hydrazide, аnthranilic acid, molecular docking, antimicrobial activity, quantum chemical parameters, structure-activity

10.29234/2308-9113-2019-7-4-94-109

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