Screening of compounds from Nigerian antidiabetic plants as protein tyrosine phosphatase 1B inhibitor

Abstract Several studies have established the antidiabetic properties of several traditional Nigerian plants, but only limited studies have elucidated their mechanism of action. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signalling pathway, is a drug target for the management of diabetes. However, to date, there is no available commercial drug with specificity for targeting PTP1B. This study sought to investigate compounds identified in Nigerian medicinal plants with therapeutic potential as inhibitors of PTP1B. A chemical library comprising more than a thousand compounds identified from Nigerian medicinal plants was docked with PTP1B; The prepared compounds were filtered using Lipinski's rule of five (RO5) and consequently used for molecular docking analysis. The binding free energy of the best ten (10) drug-like compounds was computed, then their pharmacokinetic and toxicological features were determined and compared with three standard PTP1B inhibitors. A 2D-QSAR model was constructed from an experimental dataset retrieved from literature before confirming its robustness through external validation. Finally, the reactivity and stability of the compounds, coupled with atomic regions rich in electron acceptor and donor capacity, were investigated using Jaguar fast engine. The ten top-scoring compounds had a more favourable binding affinity with PTP1B than the standard inhibitors, and they interacted with crucial residues that enhance inhibition of the protein. Generally, the natural compounds had remarkable pharmacokinetic properties and minor unwanted toxicities compared with the reference inhibitors. The external validated QSAR model (KPLS_Molprint2D_9) demonstrated that the compounds had good bioactivity against PTP1B. Through DFT calculation, blighinone was found to be the most chemically reactive compound, and electron deficit and rich regions of the compounds accepted and donated hydrogen to PTP1B amino acid residues during intermolecular interaction. The knowledge obtained in this study may help reveal natural compounds that can become potent inhibitors of PTP1B.