title: Computational insight into p21-activated kinase 4 inhibition: a combined ligand- and structure-based approach.
abstract: p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases including cancer. Targeting this kinase with specific inhibitors is of great interest in the treatment of cancer. In this study, PAK4 and its interaction with ATP-competitive inhibitors was investigated by a combined ligand- and structure-based approach. First, a ligand-based pharmacophore model was generated, consisting of five chemical features: a positive ionizable center, two hydrophobic groups, a hydrogen bond donor, and a hydrogen bond acceptor, which is consistent with available SAR information. The characteristics of the active site were then described as a topological region and used in docking of nine selected inhibitors. Combination of the pharmacophore model and results from the docking studies allowed us to weigh the various pharmacophore features and to identify the positive ionizable center as a spacer rather than an essential point. This research led to the proposal of an interaction model inside the PAK4 active site and provided guidance for the design of more potent PAK4 inhibitors.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016 (P.R. China).
authors.forename: Rui-Juan
authors.initials: RJ
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Wan-Xu
authors.initials: WX
authors.lastname: Huang
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Sheng-Fei
authors.initials: SF
authors.lastname: Jin
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhao
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Cheng
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C116367:PAK4 protein, human; D054462:p21-Activated Kinases
keywords: anticancer agents; molecular docking; p21-activated kinase 4; pharmacophore models