Insight into the selective mechanism of phosphoinositide 3‐kinase γ with benzothiazole and thiazolopiperidine γ‐specific inhibitors by in silico approaches

Abstract

The phosphoinositide 3‐kinase γ (PI3Kγ) 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 PI3Kγ‐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 PI3Kγ, a series of benzothiazole and thiazolopiperidine PI3Kγ 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 PI3Kγ inhibitor design and modification.

Theoretical Studies on the Selectivity Mechanisms of Glycogen Synthase Kinase 3β (GSK3β) with Pyrazine ATP-competitive Inhibitors by 3DQSAR, Molecular Docking, Molecular Dynamics Simulation and Free Energy Calculations

“…At last, a 30 ns NPT MD simulation was performed, using the SHAKE algorithm to bind all the bonds involving hydrogen and the time step was set to 2.0 fs. Coordinates were saved every 10 ps [35].…”

Targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors

“…The inhibitors of this series had evolved from a reported pan‐PI3K inhibitor with a phenylthiazole core 34 . To uncover the SAR of these PI3Kγ‐selective inhibitors, Zhu et al 95 reported a theoretical study by utilizing multiple in silico methods including molecular docking, molecular dynamics (MD) simulations and binding free energy calculations (Figure 11). Initially, 40 compounds were docked into the ATP‐binding pocket of PI3Kγ using three different docking protocols: rigid receptor docking, induced‐fit docking, and quantum mechanics‐polarized ligand docking 96,97 .…”

“…The binding structures predicted by induced‐fit docking were analyzed by MD simulations, MM/GBSA binding free energy calculations, and free energy decomposition 98,99 . The SAR analysis could identify not only the residues vital for PI3Kγ binding, but also the residues that are important for PI3Kγ isoform selectivity 95 . Recently, this group reported another improved SAR model 39 .…”

Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR, Molecular Docking and Molecular Dynamics Simulation

“…ΔG GB was calculated by the Generalized Born (GB) model with the parameters developed by Onufriev et al (igb = 2); [43] ΔG GA was estimated based on the solventaccessible surface area (SASA) with a fast linear combination of the pairwise overlap (LCPO) algorithm using a probe radius of 1.4 Å: [44] ΔG SA = 0.0072 × ΔSASA; À TΔS the change of conformation entropy upon ligand binding would not be calculated here because of expensive computational cost and low prediction accuracy. [45][46][47][48][49] In the ΔG GB calculations, the exterior dielectric constant was set to 80, and the solute dielectric constant was set to 1. [50,51] All energy components were calculated using the MM_PBSA program of AMBER16 based on 5000 snapshots evenly extracted from 50 to 100 ns.…”