Molecular design, ADMET evaluation, and molecular dynamic simulation of some potent sulfonamide-based compounds as anti-tuberculosis agents

Tuberculosis (TB) is a chronic bacterial infection caused by Mycobacterium tuberculosis, affecting millions of people worldwide. Despite the availability of anti-TB drugs, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains has become a significant public health concern. Therefore, there is an urgent need to discover and develop new anti-TB agents with improved efficacy and reduced toxicity. In this study, we use computational methods to identify and design new chemical entities that could be effective anti-tuberculosis agents. The developed model meets numerous organizations' recommendations for statistically valid QSAR, with R² values of 0.990 and 0.978 for internal and external validation, respectively. The designed molecules 29f and 29l exhibit higher binding affinities (∆G) of -37.15 kcal/mol and -37.31 kcal/mol, respectively, when compared to rifampin as the reference drug (RC) with ∆G of -24.13 kcal/mol, which indicates that it is more stable than RC. ADMET evaluation shows improved therapeutic qualities of these newly developed compounds, demonstrated by a reduced maximum acceptable dosage. Further validation was carried out via molecular dynamic simulation, and these analyses prove that changes in protein conformation and dynamics as a response to ligand binding provide an in-depth view of the molecular mechanisms that determine the ligand’s efficacy and protein roles.