Identification of Natural Inhibitors against the Mycobacterium tuberculosis Proteasome: Computational Study

INTRODUCTION: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health challenge. In this study, the Mtb proteasome was targeted as a promising site for novel drug development. METHODS: A total of 190,295 natural compounds from the ZINC database were screened using a systematic approach involving Lipinski's rule of five, SwissADME, pkCSM analysis, PyRx, and molecular dynamics simulation to identify potential drug candidates. RESULTS: Finally, five compounds, namely, ZINC14688701, ZINC299835179, ZINC14638395, ZINC299839873, and ZINC14638400, were identified based on physicochemical, pharmacokinetics, drug-likeness properties, and free energy of binding. Among these, ZINC14688701 showed the highest free energy of binding (-9.3 kcal/mol) with the selected target Mtb proteasome through the amino acid residues Thr1, Arg19, Ser20, Thr21, Val31, Lys33, Gly47, Thr48, Ala49, Leu99, Ser141, and Ala180. DISCUSSION: Finally, the complex 'Mtb proteasome-ZINC14688701' was studied using Molecular Dynamics simulation (MD simulation) for 50 ns, in which RMSD, RMSF, Rg, H-bonds, and SASA showed complex stability. Physicochemical evaluations revealed that the compounds are non-toxic with favorable drug-likeness. Exploring the antibacterial natural inhibitors offers a promising strategy for novel drug development against infectious diseases. CONCLUSION: These findings suggest a potential inhibitor of Mtb proteasome that could be used for TB treatment.