IN SILICO DESIGN OF 1,3,5-TRIAZINE DERIVATIVES AS ENOYL ACYL CARRIER PROTEIN REDUCTASE INHIBITORS

Divya Menon* and Supriya Mahajan

ABSTRACT

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. It affects millions of people worldwide. Isoniazid (INH) is a frontline antitubercular agent. It requires activation by the enzyme catalase-peroxidase (KatG) to convert to an active form, which forms an adduct with NADH, to inhibit the enzyme enoyl acyl carrier protein reductase (InhA). Mutations in the KatG enzyme has resulted in the development of isoniazid resistant strains of the organism. A series of 1,3,5-triazine derivatives were designed in silico and docked in the active site of the enzyme enoyl ACP reductase. These compounds were designed as direct inhibitors of the enzyme. Direct InhA inhibitors require no prior activation by any enzyme. The interaction of 24 compounds in the active site of the enzyme was studied. It was observed that some of the compounds exhibited hydrogen bond formation with the residue Tyr158, which is a conserved feature among the inhibitors of this enzyme. The potential to inhibit the enzyme was analyzed on the basis of the Glide Score (G-Score), hydrogen bonding and van der Waals interaction. Out of the 24 compounds, the ones with good G-score would be synthesized and their mechanism by inhibition of the enoyl ACP reductase would be confirmed subsequently.

Keywords: Tuberculosis, InhA, direct inhibitors, triazine derivatives, Glide score.