title: Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers.
abstract: Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.
authors.affiliation: a Department of Genetics & Biotechnology , Osmania University , Hyderabad , Andhra Pradesh , India .|b Param Bioinformatics , Hyderabad , Andhra Pradesh , India .|c VAC Biotechnologies , Hyderabad , Andhra Pradesh , India .
authors.forename: Aravind
authors.initials: A
authors.lastname: Setti
authors.affiliation: a Department of Genetics & Biotechnology , Osmania University , Hyderabad , Andhra Pradesh , India .|c VAC Biotechnologies , Hyderabad , Andhra Pradesh , India .
authors.forename: M J Vijay
authors.initials: MJ
authors.lastname: Kumar
authors.affiliation: d Department of Biochemistry , Indian Institute of Science , Bangalore , Karnataka , India , and.
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Babu
authors.affiliation: a Department of Genetics & Biotechnology , Osmania University , Hyderabad , Andhra Pradesh , India .
authors.forename: A
authors.initials: A
authors.lastname: Rasagna
authors.affiliation: a Department of Genetics & Biotechnology , Osmania University , Hyderabad , Andhra Pradesh , India .
authors.forename: M G R Devi
authors.initials: MG
authors.lastname: Prasanna
authors.affiliation: e Microbial Resources Division , Institute of Bioresources & Sustainable Development , Imphal , Manipur , India.
authors.forename: T A Phazna
authors.initials: TA
authors.lastname: Devi
authors.affiliation: a Department of Genetics & Biotechnology , Osmania University , Hyderabad , Andhra Pradesh , India .
authors.forename: Smita C
authors.initials: SC
authors.lastname: Pawar
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D021122:Protein Subunits; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits
keywords: ADME; Glide; Molegro Virtual Docker; PI3K AKT pathway inhibitors; homology modeling; molecular docking; molecular dynamics; p110 delta structure