Journal of Antimicrobial Chemotherapy

Abstract

Objectives To design new low nanomolar antitubercular agents inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase and to characterize the protein – ligand interactions using computer-based molecular simulations. Methods A TMPKmt – inhibitor complex has been prepared from 3D X-rays crystal structure of enzyme – dTMP (1GSI.pdb) for a training set of 15 TMDs with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR Pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. Finally the ADME profile of the best hits has been predicted. Results From Molecular Modelling investigations the agreement between free energy of complexation (∆∆Gcomp) and Ki values explains some 94% of the TMPKmt inhibition (pKi = - 0.2924 ∆∆Gcomp + 3.234; R2 = 0.94) and for the PH4 model (pKi = 1.0206 × pKi pred – 0.0832, R2 = 0.92). The analysis of contributions from active site residues suggested a substituted phenyl 5 – position of pyrimidine ring and various groups at 5’ position of the ribose. The best inhibitor reached a predicted ca 0.2 nM. The ADME profile of the designed compounds is better than those of current antitubercular agents. Conclusions The computational approach through the combined use of Molecular Modelling and PH4 is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antitubercular agents.