Computational Design and Evaluation of N-Aryl Oxamic Acid Derivatives Targeting Mycobacterium Tuberculosis Protein Tyrosine Phosphatase B (PtpB): 2D-QSAR, Molecular docking, MD Simulations, DFT, and Pharmacokinetic Profiling

Tuberculosis (TB), caused by Mycobacterium tuberculosis , continues to pose a significant public health burden worldwide, especially with the rising prevalence of multidrug-resistant and extensively drug-resistant strains. This study presents an integrative computational approach for the design and evaluation of N-aryl oxamic acid derivatives targeting Protein Tyrosine Phosphatase B (PtpB), a key virulence factor in M. tuberculosis . A predictive 2D-QSAR model was developed and validated using multiple statistical parameters, demonstrating high internal consistency and external predictivity. Molecular docking identified several potent ligands, notably compounds L8 and L18, which exhibited strong binding affinities. These findings were supported by 100 ns molecular dynamics simulations, confirming the structural stability of ligand–protein complexes. Complementary DFT analysis provided insight into electronic properties of the lead compound, revealing a moderate HOMO–LUMO energy gap (3.68 eV), high electrophilicity, and favourable reactivity descriptors, supporting its potential for biological interaction. Ten newly designed analogues (D1–D10) were subsequently screened, with D5 and D2 showing the most favourable docking profiles. In silico ADMET analysis revealed excellent pharmacokinetic attributes, including high intestinal absorption, favourable bioavailability, no toxicity and CYP450 enzyme inhibition. All investigated molecules complied with Lipinski’s Rule of Five criteria, exhibiting favourable drug-likeness profiles along with acceptable synthetic feasibility. Collectively, compounds L18, D5, and D2 emerged as promising candidates for further development. This study highlights the effectiveness of combining QSAR modelling, docking, dynamics, and ADMET profiling in early-stage antitubercular drug discovery.