Structure based virtual screening and discovery of novel inhibitors against FabD protein of Mycobacterium tuberculosis

Abstract

The highly flexible nature of Mycobacterium tuberculosis (Mtb) can be owed to its tough cell wall and multiple gene interaction system which makes it resistant to frontline TB drugs. Mycolic acids are the key components of the unique cell wall that protects the organism from external threats. Proteins of the fatty acid synthesis pathway are evolutionarily conserved that enables cellular survival in harsh conditions and hence have become attractive targets. Malonyl Co-A Acyl carrier protein transacylase (FabD; MCAT, EC2.3.1.39) is an enzyme in the branching point of the unique and vast fatty acid synthase (FAS-I and FAS-II) systems of Mtb. In the present investigation, in-silico structure based drug discovery with the compounds from an open source library (NPASS) is used for target fishing and employed to understand the interaction with the target protein FabD. The potential hit compounds were filtered using exhaustive docking, considering the binding energy, key residue interaction and drug likeness property. Three compounds from the library namely NPC475074 (Hit 1), NPC260631 (Hit 2) and NPC313985 (Hit 3) with binding energies −14.45, −13.29 and −12.37 respectively were taken for molecular dynamic simulation. The results suggested that Hit 3 (NPC313985) has stable interaction with FabD protein. This article further elaborates the interaction of the identified novel compounds Hit 1 and Hit 3 along with the other known compound (Hit 2) against Mtb FabD protein. The hit compounds identified from this study could be further evaluated against mutated FabD protein and considered for in-vitro evaluation. Communicated by Ramaswamy H. Sarma