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.