Computational Modeling of Novel Phosphoinositol‐3‐kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D‐QSAR

Abstract

Phosphoinositol‐3‐kinase γ (PI3Kγ) is a member of the class‐IB PI3K superfamily and plays a significant role in G‐protein‐coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3Kγ in tumor‐associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3Kγ remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3Kγ for cancer treatment. In this study, we have reported the critical interactions of isoindolinone‐based inhibitors with PI3Kγ by docking and molecular dynamics simulations. The binding free energy of the receptor‐ligand complex was calculated using molecular mechanics/Poison‐Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure–activity relationship of the inhibitors. The CoMFA (q2 = 0.681 and r2 = 0.968) and CoMSIA (q2 = 0.665 and r2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption‐distribution‐metabolism‐excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3Kγ inhibitors.

Structure–activity relationship and in silico development of c‐Met kinase inhibitors

“…Molecular docking was performed using AutoDock‐4.2 in the graphical interface of AutoDockTools‐1.5.6 26 according to our previous studies 27–28 . The foretinib bound c‐Met coordinate file (PDB: 6SDC) 29 with a resolution of 1.67 Å was retrieved from the PDB database.…”

“…Molecular docking was performed using AutoDock-4.2 in the graphical interface of AutoDockTools-1.5.6 26 according to our previous studies. [27][28] The foretinib bound c-Met coordinate file (PDB: 6SDC) 29 with a resolution of 1.67 Å was retrieved from the PDB database. Water molecules, ions, and ligands from the crystallographic solution were removed, followed by the preparation of protein and ligand into separate files.…”

Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3

“…Compound C31 was the most active compound in the dataset and selected as the representative candidate for the docking study. To prepare the 3D structure of C31, Sybyl X 2.1 was used to sketch, minimize, and assign gasteiger charges as described in earlier studies [ 19 , 20 ]. The receptor was prepared using the structure preparation tool performed with the Amber7 99 force field.…”

3D-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors

“…The all-atom MD simulation of the protein-ligand complex was conducted by GROMACS version: 2019.5 [19], using the Amber ff03 force field, according to earlier studies [20,21]. TAE226 or C36 was parameterized using ACEPYPE [22], where atom types were assigned as GAFF types and AM1-BCC partial charge model.…”