In silico identification of novel PTP1B inhibitors by the investigation of molecular mechanism, QSAR, and DFT studies.

Protein tyrosine phosphatase 1B (PTP1B) is a well-known and promising drug target involved in the negative regulation of insulin and leptin signaling, and new anti-diabetic molecules for the treatment of type 2 diabetes are directly in its hands. A series of PTP1B inhibitors was discovered and characterized using in silico techniques, including virtual screening, molecular docking, ADMET profiling, toxicity prediction, VEGA-QSAR analysis, molecular dynamics (MD) simulation, and density functional theory (DFT) calculations. A starting library of 1000 anti-diabetic compounds was screened, and PubChem CID 44560696 was identified as the most successful hit. The most potent inhibitor was then identified as CID 44560744 through chemical analogy-based refinement, with a binding free energy of - 9.13 kcal/mol and the ability to form several stabilizing hydrogen bonds and hydrophobic interactions with the key catalytic residues. DFT-optimized geometry and docking revealed that the lead compound shows high stability and strong PTP1B inhibition, showing superior binding affinity compared to ursolic acid, which exhibited a lower binding energy of - 6.34 kcal mol