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

Chem Biodivers. 2019 Jul;16(7):e1900105. doi: 10.1002/cbdv.201900105. Epub 2019 Jun 21.

Abstract

Phosphoinositide 3-kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform-selective inhibitors were analyzed by a systematic computational method, combining 3D-QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure-activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.

Keywords: 3D-QSAR with CoMFA; PI3Kγ selective inhibitor; biological activity; molecular docking; molecular dynamic simulation; rational design.

MeSH terms

  • Drug Design*
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors