Structural and Electronic Factors Influencing the Selective Inhibition of COX-2
Abstract
Structural and electronic factors influencing the inhibition of cyclooxygenase-1 and -2 (COX-1/COX-2) were studied by means of Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking and Density Functional Theory (DFT). A series of structurally diverse compounds containing 209 molecules were classified in accordance with their inhibiting properties, as selectively inhibiting and non-selectively inhibiting COX-2 receptor agents (110 and 99 molecules, correspondingly). The results obtained from the ETM-NN calculations gave us possibility of selecting those pharmacophoric molecular fragments, which allow for the search of new selective inhibitors of COX-2 with high probability of realization. The final selection of pharmacophores and anti-pharmacophores found was taken as a basis for a system designed for the COX-2 inhibitory activity prediction. Analysis of the electron density distribution showed that more effective binding with COX-2 receptor was observed for selective inhibitors. To make an assessment of these interactions, calculations of stabilization energies were carried out for the ligand-receptor complexes. From the results of the docking and from the analysis of electronic structures of active sites of enzymes, some peculiarities of ligand-receptor binding and its influence on the selectivity of the COX-2 relative to COX-1 inhibition were elucidated. 95% of compounds were recognized correctly, as the most active ones, by the system of…
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