Pharmacophore optimization and design of competitive inhibitors of thymidine monophosphate kinase through molecular modeling studies.

A series of N(1) -(4-substituted-benzyl)-pyrimidines were subjected to 2D and 3D quantitative structure-activity relationship analyses. Statistically significant models were generated, and the most robust model for 2D quantitative structure-activity relationship was obtained using simulated annealing-multiple linear regression. The physicochemical descriptors, viz., slogp, estate descriptors like SaaCHE index and SdsCHE index contribute significantly to the biological activity. The pharmacophore requirements for selective inhibition of Mycobacterium tuberculosis thymidine monophosphate kinase were optimized using the information derived from 2D and 3D quantitative structure-activity relationship studies. With the results from the studies, we have designed new chemical entities using the CombiLib Tool of V-Life Molecular Design Suite. In addition, using structure-based drug design, the distances between interacting groups of ligands and amino acid residues of the protein Mycobacterium tuberculosis thymidine monophosphate kinase (PDB ID:1W2H) were thoroughly analyzed. Thus, we have successfully replaced the sugar moiety with substituted aromatic ring on N1 of thymidine. Thorough studies on substitution pattern around pyrimidine ring were carried out.