Trigger factor, as a chaperone protein, is required for survival of Mycobacterium tuberculosis (M.tb) in a stressed environment. This protein interacts with various partners in both the pre- and the post-translation processes, yet the crystal structures of the M.tb trigger factor remain unresolved. In this study, we developed a homology model of M.tb trigger factor to facilitate the discovery and design of inhibitors. To validate the model, we employed several methodologies, including Ramachandran plot and molecular dynamics simulations. The simulations showed a stable trajectory, indicating the accuracy of the model. The active site of M.tb Trigger Factor was identified based on site scores, and virtual screening of over 70,000 compounds led to the identification of two potential hits: HTS02984 (ethyl 2-(3-(4-fluorophenyl)ureido)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate) and S06856 ((E)-N-(4-((2-(4-(tert-butyl)benzoyl)hydrazono)methyl)phenyl) acetamide). These compounds showed strong binding affinity and energy scores, and their chemical descriptors were evaluated. Our study provides a reliable computational model for M.tb Trigger Factor and identifies two potential inhibitors for this crucial protein, which could aid in the development of novel therapies against tuberculosis.Communicated by Ramaswamy H. Sarma.
Keywords: Trigger factor; chaperones; molecular dynamics simulations; tuberculosis; virtual screening.