Abstract

MOLECULAR DOCKING STUDIES OF 1,3,4-THIADIAZOLES AS NOVEL MALATE SYNTHASE INHIBITORS AS POTENTIAL ANTITUBERCULAR AGENTS

Annapoorna Vadivelu*, V.Gopal and C. Uma Maheswara Reddy

ABSTRACT

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, The malate synthase (MS), one of the enzymes in the glyoxylate shunt and their potential inhibitors correspond to one of the most promising targets in the search for novel mode of antibiotics action and was selected as a specific anti tubercular target. Binding modes of a series of 1,3,4-Thiadiazoles as malate synthase inhibitors have been identified by molecular modeling techniques. We performed Insilco molecular docking using Schrodinger LLC., software (GLIDE XP). We performed rescoring of the GLIDE scores using PRIME MM-GBSA module of Schrodinger LLC. This study also helped us to understand the inhibitor mechanisms of PDF structure. The results indicate that 1,3,4-Thiadiazoles for addition to hydrogen bonding interactions, Asn233, Asn234, Ser111 and Asp531 amino acid residues of malate synthase are responsible for governing inhibitor potency of the compounds. The docked values for Glide using XP were –6 and -2.0 Kcal/mol for moleculeB6, B18 and B9.The corresponding rescored values (binding energy) values were -61 Kcal/mol in XP for B18 and the molecule B9 showed values of -62 Kcal/mol in XP scores. ADME predictions of compounds were done with Qikprop 3.2 tool available in Schrödinger 9.0 ver. The information generated from the present study should be useful in the design of more potent malate synthase inhibitors.

Keywords: MMGBSA, Docking, ADME predictions, Malate synthase