title: Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening.
abstract: Preclinical data and tumor specimen studies report that AKT kinases are related to many human cancers. Therefore, identification and development of small molecule inhibitors targeting AKT and its signaling pathway can be therapeutic in treatment of cancer. Numerous studies report inhibitors that target the ATP-binding pocket in the kinase domains, but the similarity of this site, within the kinase family makes selectivity a major problem. The sequence identity amongst PH domains is significantly lower than that in kinase domains and developing more selective inhibitors is possible if PH domain is targeted. This in silico screening study is the first time report toward the identification of potential allosteric inhibitors expected to bind the cavity between kinase and PH domains of Akt1. Structural information of Akt1 was used to develop structure-based pharmacophore models comprising hydrophobic, acceptor, donor and ring features. The 3D structural information of previously identified allosteric Akt inhibitors obtained from literature was employed to develop a ligand-based pharmacophore model. Database was generated with drug like subset of ZINC and screening was performed based on 3D similarity to the selected pharmacophore hypotheses. Binding modes and affinities of the ligands were predicted by Glide software. Top scoring hits were further analyzed considering 2D similarity between the compounds, interactions with Akt1, fitness to pharmacophore models, ADME, druglikeness criteria and Induced-Fit docking. Using virtual screening methodologies, derivatives of 3-methyl-xanthine, quinoline-4-carboxamide and 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol were proposed as potential leads for allosteric inhibition of Akt1.
authors.affiliation: Bogazici University, Department of Chemical Engineering, 34342 Istanbul, Turkey. Electronic address: oyagursoy@gmail.com.
authors.forename: Oya Gursoy
authors.initials: OG
authors.lastname: Yilmaz
authors.affiliation: Bogazici University, Department of Chemical Engineering, 34342 Istanbul, Turkey. Electronic address: elif.ozkirimli@boun.edu.tr.
authors.forename: Elif Ozkirimli
authors.initials: EO
authors.lastname: Olmez
authors.affiliation: Bogazici University, Department of Chemical Engineering, 34342 Istanbul, Turkey. Electronic address: ulgenk@boun.edu.tr.
authors.forename: Kutlu O
authors.initials: KO
authors.lastname: Ulgen
mesh_terms: D000495:Allosteric Site; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Allosteric Akt inhibitor; Allosteric kinase inhibitor; Induced fit docking; Molecular docking; Pharmacophore; Virtual screening