Computational Identification of Inhibitors Targeting Hercynylcysteine Sulfoxide Lyase of <i>Mycobacterium tuberculosis</i> : Structure-Guided Virtual Screening and Molecular Dynamics Simulation Studies

Tuberculosis (TB) is a contagious airborne disease characterized by an increasing incidence of multidrug resistance. TB is a leading cause of bacterial infection-related deaths worldwide. Since the available drugs are not effective and the drug targets are acquiring resistance, there is a necessity to discover new and promising drug targets and lead molecules to combat drug-resistant TB. In this context, our study explored the possibility of utilizing hercynylcysteine sulfoxide lyase, which is one of the major redox systems that prevents bacteria from maintaining redox homeostasis. However, the complete mechanism of Mtb redox homeostasis remains unknown; hence, we constructed a model of the target protein to understand its structural features and probable mechanisms. MD simulations were conducted for 100 ns to examine the structural characteristics and structural integrity of the modeled three-dimensional protein structure. Furthermore, we identified three potent plant phytochemicals using a structure-guided virtual-screening strategy. The identified phytochemicals (CID: 137, 119 and 449468) were nontoxic and showed stable binding in MMGBSA and molecular dynamics simulation analysis. Overall, our results indicate that these three phytochemicals could bind to the functional site of hercynylcysteine sulfoxide lyase to impede its biological function, and further experimental validation is needed to validate our computational findings.