Computational evaluation of glutamine synthetase as drug target against infectious diseases: molecular modeling, substrate-binding analysis, and molecular dynamics simulation studies

Glutamine synthetase is an enzyme that catalyzes the condensation of glutamate and ammonia to form glutamine in the presence of adenosine triphosphate. The wealth of structure-related information about glutamine synthetase across the species is endorsing it as emerging potential drug target. Owing to its well-characterized role in metabolism of Mycobacterium, various high throughput screening studies have been aimed at the identification of inhibitors against MtGS. The present work is focussed on comparative sequence and structural studies of glutamine synthetase and its evaluation as drug target against the infectious diseases. We have done molecular modeling studies of glutamine synthetase of Leishmania and Plasmodium. The structure models and molecular dynamics simulations studies shed light on to the binding modes of substrates viz. adenosine diphosphate, glutamate, ammonia, and metal ions. The comparative studies of MtGS, HsGS, LmGS, and PvGS helped in better understanding of prospects of structure-based inhibitor design. The results suggest that amino acid-binding site is highly conserved, whereas nucleotide-binding site possess subtle variations and thus offers opportunity for specific inhibitor design. Therefore, present study suggests that broad spectrum glutamine synthetase inhibition is feasible and it is potential drug target against infectious diseases.