Investigation of the «Structure – analgesic activity» Relationship Using Molecular Docking for Cyclooxygenases 1 and 2 in the Series 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thiones

Introduction. Molecular modeling methods are very popular in the scientific community at the present time. The value of the pharmacological action depends on the affinity of the substance to the biological target. Molecular docking makes it possible to assess the degree of affinity of the studied compound with the active center of the molecular target. The enzyme cyclooxygenase (COX) plays a key role in the cascade of synthesis of proinflammatory cytokines and, as a consequence, in pain.

Aim. To identify the dependence "structure – analgesic activity" using the method of molecular docking for cyclooxygenase type 1 and type 2 in the series of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions.

Materials and methods. 19 compounds 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions are objects of research The study of the interaction of tetrahydropyridine derivatives with COX 1 and 2 was carried out by the method of molecular docking by the AutoDock 4 program using scoring functions.

Results and discussion. Molecular docking of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions (I–XIX) with COX 1 and 2 is described. Quantitative studies of the "structure – analgesic activity" in the studied series of compounds of the dependence of experimental values of analgesic activity (АА_ex.) on scoring functions (Be_COX1, Ki_COX1, Be_COX2, Ki_COX2) and physico-chemical descriptors (log P_pred., рКа_pred., рКv_pred.) were performed. By checking on an independent sample of 5 compounds, equation No. 3 (АА_pred. 3 = 32,6215 – 4,4894 × Be_cox1 + 0,0066 × Ki_cox1 + 3,6032 × log P_pred. (R = 0,854, F = 9,01, S = 7,73, Q²_LOO = 0,53) was found, with a high value of the correlation coefficient of the predicted values АА_ex. with experimental values (R_pred. = 0,878) and a minimum forecast error (S_pred. = 6,74).

Conclusion. The "structure-activity" models for predicting analgesic activity in a series of 5-N-arylaminocarbonyl-6-(get)aryl-4-methyl-1,2,3,6-tetrahydropyrimidine-2-thions are obtained. The result of the prediction of biological activity is confirmed by the values of the correlation coefficient (R) obtained when testing models on independent samples.

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