Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

Abstract

We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPK mt ), by means of structure-based molecular design. 3D models of TMPK mt -inhibitor complexes have been prepared from the crystal structure of TMPK mt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (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. From molecular modeling investigations, the agreement between free energy of complexation ( ΔΔGcom ) and Ki values explains 94% of the TMPK mt inhibition ( pKi=-0.2924ΔΔGcom+3.234;R2=0.94 ) by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4) model ( pKi=1.0206×pKipred-0.0832, R2=0.92 ). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted Ki of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.