title: Docking simulation study and kinase selectivity of f152A1 and its analogs.
abstract: f152A1 is a potent inhibitor of MAP kinases and TNFα-transcription. When f152A1 and its analogs are assayed against ERK2, MEK1, and MEKK1, these compounds show different inhibition profiles. It is considered that the highly reactive cis-enone moiety and modifications of the 14-membered resorcylic lactone ring may determine their kinase selectivity and potency. In order to clarify the different potencies of these compounds toward MAP kinases, conformational analysis, molecular orbital studies, and docking simulation studies using model structures of ERK2, MEK1, and MEKK1 have been performed. These studies have revealed that (i) ligand binding does not depend on chemical bonding but on molecular interaction (molecular orbital analysis), (ii) the cis-enone moiety of inhibitors is in the range of Michael addition reaction with the Cys166 residue in ERK2 (docking simulation study), and (iii) molecular shape of M1(8) conformations is the best fit for the ATP binding site of kinases. Considering the molecular docking analysis of these inhibitors in these kinases, molecular shape will be most important to their corresponding kinases activities.
authors: Eisai Tsukuba Research Laboratories, 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors: Megumi
authors: M
authors: Ikemori-Kawada
authors: Atsushi
authors: A
authors: Inoue
authors: Masaki
authors: M
authors: Goto
authors: Yuan John
authors: YJ
authors: Wang
authors: Yoshiyuki
authors: Y
authors: Kawakami
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C118715:LL Z1640-2; D007783:Lactones; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases