Computational design and evaluation of anilinoquinazoline derivatives as potential anti-tuberculosis agents: DFT, docking, ADMET, and molecular dynamics simulation

Tuberculosis remains a major global health challenge, driven by the emergence of drug-resistant Mycobacterium tuberculosis strains and the limited efficacy of existing therapies. Protein tyrosine phosphatase B (PtpB), a secreted virulence factor essential for immune evasion and intracellular survival, represents an attractive molecular target for the development of novel antitubercular agents. In this study, an integrated in silico approach was employed to identify potential PtpB inhibitors from a series of anilinoquinazoline derivatives. Molecular docking–based virtual screening of thirty-five reported compounds was performed to evaluate their binding affinity toward the PtpB active site. Several ligands exhibited stronger docking scores than the reference drugs isoniazid and OMTS, with compound 10 emerging as a promising hit. Detailed interaction analysis supported its selection as a lead scaffold for further optimization. Consequently, compound 10 was used as a template to design nine novel analogues, among which compound 10b demonstrated markedly improved binding affinity and a favourable interaction profile within the active site. Molecular dynamics simulations over 100 ns confirmed the structural stability of the 10b–PtpB complex, as reflected by low RMSD fluctuations and persistent interactions with key catalytic residues. MM-GBSA free energy calculations further supported the enhanced binding propensity of compound 10b. Density functional theory (DFT) calculations revealed reduced HOMO–LUMO energy gaps for the lead compounds, indicating enhanced chemical reactivity. Furthermore, drug-likeness and ADMET profiling showed that both the hit compound and the designed analogues comply with Lipinski’s rule of five and possess acceptable pharmacokinetic and safety characteristics. Collectively, these findings identify compound 10b as a promising PtpB inhibitor with favourable stability, electronic characteristics, and pharmacokinetic properties, supporting its recommendation for further experimental validation as a potential antitubercular lead. • Novel anilinoquinazoline analogues were designed as potent inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatase B (PtpB). • Compound 10b demonstrated superior binding affinity (-139.596 kcal/mol) and stability compared to the reference drug isoniazid. • DFT calculations revealed enhanced reactivity with a reduced energy band gap (3.76 eV) favouring biological interactions. • Molecular dynamics simulations confirmed stable binding with low RMSD fluctuations (1.7-1.9 Å) over 100 ns. • Comprehensive profiling predicted favourable ADMET characteristics and synthetic accessibility for the lead compounds