Molecular modeling studies of Fatty acyl-CoA synthetase (FadD13) from Mycobacterium tuberculosis--a potential target for the development of antitubercular drugs.

Tuberculosis (TB) is a global health problem and the situation has become more precarious due to the advent of HIV infections and continuous rise in the number of multi-drug resistant strains of Mycobacterium tuberculosis (M. tb). Biochemical studies on Fatty Acyl-CoA Synthetases (FadD13), one of the gene products of mymA operon, have provided insights into the involvement of this protein in the activation of fatty acids. Due to non-availability of the crystal structure of FadD13, we have employed in silico approaches to resolve and characterize the structure of this important protein of M. tb. A three dimensional model of M. tb FadD13 was predicted by a de novo structure prediction server that integrates fragment assembly with SimFold energy function. With the aid of molecular mechanics and dynamics methods, the final model was obtained and assessed subsequently for global and local accuracy by various assessment programs. With this model, a flexible docking study with the substrates was performed. Results of ligand interactions with key amino acids in the binding site are also summarized. The molecular model for the M. tb FadD13 obtained sheds light on the topographical features of the binding pocket of the protein and provides atomic insight into the possible modes of substrate recognition. The three-dimensional model of FadD13 presented here would be helpful in guiding both enzymatic studies as well as design of specific inhibitors.