title: Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through molecular simulation and structure-activity study on simplified analogs of the receptor-recognition domain.
abstract: Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase Cδ (PKCδ) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure-activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKCδ C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds.
authors.affiliation: Department of Applied Bioresource Science, The United Graduate School of Agricultural Sciences, Ehime University (Kagawa University), Kagawa 761-0795, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ashida
authors.affiliation: Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan. Electronic address: charlesy@ag.kagawa-u.ac.jp.
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.affiliation: Division of Applied Bioresource Science, Graduate School of Agriculture, Kagawa University, Kagawa 761-0795, Japan.
authors.forename: Chise
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawanami
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D001665:Binding Sites; D020536:Enzyme Activators / Q000737:chemistry*; D004952:Esters / Q000138:chemical synthesis; D006860:Hydrogen Bonding; D008024:Ligands; D008235:Lyngbya Toxins / Q000737:chemistry*; D008567:Membranes, Artificial; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010703:Phorbol Esters / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D011485:Protein Binding; D000072417:Protein Domains; D051745:Protein Kinase C-delta / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D004952:Esters; D008024:Ligands; D008235:Lyngbya Toxins; D008567:Membranes, Artificial; D010703:Phorbol Esters; D010718:Phosphatidylserines; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; C006610:aplysiatoxin; D051745:Protein Kinase C-delta
keywords: Aplysiatoxin; Molecular dynamics simulation; Protein kinase C; Structure–activity study; Tumor promoter