Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 93, Issue 5, Pages 818-831Publisher
WILEY
DOI: 10.1111/cbdd.13469
Keywords
MM-GBSA; molecular docking; molecular dynamic simulation; PI3K gamma; selective inhibitor
Funding
- National Natural Science Foundation of China [21807049]
- Fundamental Research Funds for the Central Universities [JUSRP11892]
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The phosphoinositide 3-kinase gamma (PI3K gamma) has been verified to be a potential drug target for the treatments of various human physical disorders. Although received lots of attention, the development of PI3K gamma-selective inhibitors is still a challenging subject because of its unique protein structural features. Aiming to uncover the interaction mechanism between the selective inhibitors and PI3K gamma, a series of benzothiazole and thiazolopiperidine PI3K gamma isoform-selective inhibitors were studied with an integrated in silico strategy by combining molecular docking, molecular dynamic simulations, binding free energy calculations, and decomposition analysis. Firstly, three molecular docking models, including rigid receptor docking, induced fit docking (IFD), and quantum mechanical-polarized ligand docking, were respectively, built, and the IFD preliminarily predicted the docking poses of all studied inhibitors and roughly analyzed the binding mechanism. Secondly, four binding complexes with representative inhibitors were selected to perform molecular dynamic simulations and free energy calculations. The predicted binding energies were consistent with the experimental bioactivities and different binding patterns between potent and weak inhibitors were uncovered. Finally, through the Molecular Mechanics/Generalized Born Surface Area binding free energy decomposition, residue-inhibitor interactions spectra were obtained and several key residues contributing to favorable binding were highlighted, which provides valuable information for rational PI3K gamma inhibitor design and modification.
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