AbstractType 2 diabetes mellitus (T2D) remains a major global health problem, requiring the development of effective therapeutic approaches targeting multiple targets. In this study, 41 PTP1B inhibitors were analyzed using a computational framework combining ADMET screening, network pharmacology, molecular docking, and molecular dynamics simulations. Evaluation of the ADMET properties of the study series led to the elimination of four compounds due to their unfavorable toxicity profiles. This resulted in a set of 37 molecules for subsequent analyses. Network pharmacology, which includes the development of protein-protein interaction (PPI) networks, genetic ontology (GO) analysis, and enrichment of KEGG pathways, revealed biological mechanisms and signaling pathways associated with glucose metabolism and insulin resistance, highlighting the importance of major regulators such as PPARG and AKT1. To validate the docking protocol, the co-crystallized ligand was re-docked into the binding site, yielding RMSD values below 2.0 Å. In addition, molecular docking performed on PTP1B (4Y14), AKT1 (6HHF) and PPARG (5Y2T) identified three particularly efficient ligands (MY15, MY17 and MY30), which demonstrate high binding affinity and remarkable interaction profiles within active sites. To further evaluate the dynamic stability of the most promising complex, a molecular dynamics simulation was performed on the MY17-PPARG (5Y2T) complex over a 100 ns period, confirming its stable binding modes and robust intermolecular interactions. Furthermore, the MM-PBSA approach demonstrated beneficial interactions for this specific complex, with a binding energy of 78.626 ㊣ 1.66 kJ/mol. This comprehensive method underlines the therapeutic potential of the studied compounds and highlights MY17 as the most promising candidate for ultimate experimental validation in the fight against type 2 diabetes.
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[Full book]Mycology in a Changing Planet: Applications and Perspectives from Southeast Asia
