Identification of Antimycobacterial Agent Using In Silico Virtual Screening, ADME Prediction, Docking, and Molecular Dynamics Simulations Approach

Background: The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery. Objective: The purpose of the present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking, followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division. Methods: The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using the Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulation studies were performed using the Schrodinger suite. The minimal inhibitory concentration of the test compounds was determined by the colorimetric method by the Resazurin Microtiter plate Assay. Results: The binding of hit molecules T5427054 and 6M356S was mainly supported by van der Waals interaction and an electrostatic component of solvation energy computed by the MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 mu g/mL. Conclusion: In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents, and further their structural modification might be improved antimycobacterial properties of hit molecules.