Comparative Modeling Studies of 1-deoxy-D-xylulose 5-phosphate Synthase (MEP pathway) from Mycobacterium Tuberculosis

Abstract

AbstractTuberculosis is a major health problem in humans because of its multidrug resistance and discovering new treatmentsfor this disease is urgently required. The synthesis of isoprenoids in Mycobacterium tuberculosis has been reported asan interesting pathway to target. In this context, 2C-methyl-D-erythritol 4-phosphate (MEP) pathway of M. tuberculosishas drawn attention. The MEP pathway begins with the condensation of glyceraldehyde 3-phosphate and pyruvate forming1-deoxy-D-xylulose 5-phosphate (DXP) which is catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS). As thereis no X-ray structure was reported for this target, comparative modeling was used to generate the three dimensionalstructure. The structure was further validated by PROCHECK, VERIFY-3D, PROSA, ERRAT and WHATIF. Moleculardocking studies was performed with the substrate (Thiamine pyrophosphate) and the reported inhibitor 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolol[1,5-a]pyrimidin-7-one) against the developed model to identify thecrucial residues in the active site. This study may further be useful to provide structure based drug design.Key words: 1-deoxy-D-xylulose 5-phosphate synthase (DXS), Homology Modeling, Molecular Docking, Drug Design,Tuberculosis