Identification of Potent Molecule for Rifampicin‐Resistant <i>Mycobacterium tuberculosis</i> using Natural Compounds by Structure‐Based Analysis

ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M. tb ), is a primary contributor to morbidity and mortality among underdeveloped countries. The spread of drug‐resistant TB is one crucial concern to world health. Mutations in rpoB, the beta subunit of M. tb 's DNA‐directed RNA polymerase (PDB ID: 6DVC), have been identified as a critical source of rifampicin (RIF) resistance. To find efficient small molecule compounds from Natural Compound Archives, this work models resistant rpoB mutants (S450L and D435V) and uses pharmacophore‐based virtual screening to pick out molecules of interest. Phase fitness evaluations from the pharmacophore‐based virtual screening were used and created 84 hits from the three‐dimensional hypothesis screening. The docking results revealed that asn:98397 more effectively inhibited the wild‐type rpoB with a score of −9.8 kcal/mol, and also the mutations S450L and D435V had interactions with scores of −9.295 and −9.670 kcal/mol, respectively. On the contrary, RIF had less interaction with the wild type: −2.767 kcal/mol, S450L: −6.676 kcal/mol, and D435V: −8.241 kcal/mol, revealing the incapability of RIF inhibition and thus showing resistance. Molecular dynamics (MD) simulations were performed on leading hit complex structures to investigate their rigidity, interconnections, and longevity. The identified phytocompound can behave as an alternative to RIF and overcome resistance.