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Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3K γ ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR, Molecular Docking and Molecular Dynamics Simulation
Author(s) -
Li Kan,
Zhu Jingyu,
Xu Lei,
Jin Jian
Publication year - 2019
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201900105
Subject(s) - docking (animal) , homology modeling , computational biology , pi3k/akt/mtor pathway , quantitative structure–activity relationship , rational design , chemistry , molecular dynamics , molecular model , phosphoinositide 3 kinase , virtual screening , biochemistry , combinatorial chemistry , enzyme , stereochemistry , signal transduction , biology , computational chemistry , genetics , medicine , nursing
Phosphoinositide 3‐kinase gamma (PI3K γ ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3K γ 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 PI3K γ , a series of PI3K γ 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 PI3K γ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3K γ inhibitors through this computational modeling and optimization.