Structure-guided multiscale evaluation of 5-nitroisatin mannich bases targeting pantothenate synthetase: DFT, ADMET, molecular docking, molecular dynamics and In Vitro antitubercular screening

AbstractAn integrated drug-discovery strategy was employed to design, synthesize, and evaluate aseries of isatinmannich bases as potential antitubercular agents, combining computationalapproaches with experimental biological screening. Structurally diverse isatinmannichderivatives were rationally designed to explore their interactions with selectedMycobacterium tuberculosis therapeutic targets and subsequently synthesized andcharacterized using appropriate spectroscopic techniques. Molecular docking studies wereperformed to investigate their binding affinity and interaction patterns within the target activesite, with particular emphasis on hydrogen bonding, hydrophobic contacts, π-interactions, andkey active-site residues. DFT calculations were carried out to examine optimized moleculargeometries, electronic properties, frontier molecular orbitals, and reactivity descriptors,providing insights into the structural features associated with biological activity. MDsimulations were further employed to assess the stability and persistence of the ligand–protein complexes under dynamic conditions. In silico ADMET profiling was performed toevaluate drug-likeness, physicochemical properties, pharmacokinetic characteristics, andpotential toxicity. The synthesized compounds were also subjected to in vitro antitubercularscreening against M. tuberculosis to determine their inhibitory potential. Integration ofdocking, DFT, MD, ADMET, and experimental findings enabled the identification ofpromising isatinmannich scaffolds and provided molecular-level insights into their potentialas antitubercular leads.