Marine Bacterial Compounds Targeting <i>Mycobacterium Leprae</i> Methyltransferase: Structural Insights and Scaffold Optimization

Abstract Leprosy remains a public health problem as a result of the increased emergence of drug‐resistant Mycobacterium leprae ( M. leprae ) strains; thus, novel therapeutic strategies are needed. This is a computational drug discovery to search for potential inhibitors of M. leprae methyltransferase, Ml2640C, from a marine bacterial compound database. Out of 2895 compounds subjected to virtual screening using MTiOpenScreen, 1500 ligands were filtered by the screening algorithms. The high binding affinity was found to lie from −11.5 to −11.2 kcal/mol with the stable binding pose for three compounds, CMNPD24471, CMNPD25830, and CMNPD21066. Further, these were authenticated through molecular dynamics, principal component analysis, and free energy landscape studies. The CMNPD24471 was the most stable complex, with the participation of hydrophobic interaction along with hydrogen bonding by crucial residues. Thirty structurally diversified analogs with a drug‐likeness score in the range between 4.5 and 6.0 and synthetic accessibility from 0.56 to 0.86 were obtained upon scaffold hopping of CMNPD24471. These findings underscore marine‐derived compounds and scaffold optimization as viable strategies for developing novel anti‐leprosy agents acting against Ml2640C.