title: Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain.
abstract: Computational modeling continues to play an important role in novel therapeutics discovery and development. In this study, we have investigated the use of in silico approaches to develop inhibitors of the pleckstrin homology (PH) domain of AKT (protein kinase B). Various docking/scoring schemes have been evaluated, and the best combination was selected to study the system. Using this strategy, two hits were identified and their binding behaviors were investigated. Robust and predictive QSAR models were built using the k nearest neighbor (kNN) method to study their cellular permeability. Based on our in silico results, long flexible aliphatic tails were proposed to improve the Caco-2 penetration without affecting the binding mode. The modifications enhanced the AKT inhibitory activity of the compounds in cell-based assays, and increased their activity as in vivo antitumor testing.
authors.affiliation: Department of Experimental Therapeutics-Unit 36, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Du-Cuny
authors.forename: Zuohe
authors.initials: Z
authors.lastname: Song
authors.forename: Sylvestor
authors.initials: S
authors.lastname: Moses
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001798:Blood Proteins / Q000737:chemistry; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003198:Computer Simulation; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010750:Phosphoproteins / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C039077:platelet protein P47; D051057:Proto-Oncogene Proteins c-akt