title: Water Molecules Increases Binding Affinity of Natural PI3Kγ Inhibitors Against Cancer.
abstract: The PI3K pathway is a signal transduction process including oncogenes and receptor tyrosine kinase regulating cellular functions i.e., survival, protein synthesis, and metabolism. In the present work, we have investigated the role of water molecules on inhibitor's binding orientation in crystal structures of PI3K pathway targets using molecular docking approach. AutoDock v4.2 docking software was employed to dock PI3Kγ and its known inhibitors viz., wortmannin, quercetin, myricetin and pyridyl-triazine. Besides, serpentine was also docked on the same binding pocket, subsequently its anticancer activity was evaluated through in vitro experiment. Docking studies have been performed in the presence as well as in absence of water molecules at the binding pocket, and results were compared with crystallographic structural data. The comparison was done on the basis of binding energy, RMSD, inhibition constant (Ki), conserved and bridging water molecules, and found that, while considering water molecules during docking experiments, it increases the binding affinity of PI3K inhibitors.
authors.forename: Pooja
authors.initials: P
authors.lastname: Sharma
authors.forename: Aparna
authors.initials: A
authors.lastname: Shukla
authors.forename: Komal
authors.initials: K
authors.lastname: Kalani
authors.forename: Vijaya
authors.initials: V
authors.lastname: Dubey
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Suaib
authors.initials: S
authors.lastname: Luqman
authors.affiliation: Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal & Aromatic Plant, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow-226015 (U.P.) India. f.khan@cimap.res.in.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D012984:Software; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014867:Water / Q000737:chemistry / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D014227:Triazines; D014867:Water; C040015:myricetin; D011794:Quercetin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D000077191:Wortmannin