title: Modeling aided design of potent glycogen phosphorylase inhibitors.
abstract: Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000, Rahway, NJ 07065, USA. qiaolin_deng@merck.com
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Lu
authors.forename: Joann
authors.initials: J
authors.lastname: Bohn
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Ellsworth
authors.forename: Robert W
authors.initials: RW
authors.lastname: Myers
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Geissler
authors.forename: Georgianna
authors.initials: G
authors.lastname: Harris
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Willoughby
authors.forename: Kevin
authors.initials: K
authors.lastname: Chapman
authors.forename: Brian
authors.initials: B
authors.lastname: McKeever
authors.forename: Ralph
authors.initials: R
authors.lastname: Mosley
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000495:Allosteric Site; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007854:Lead / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D011994:Recombinant Proteins; D007854:Lead; D000249:Adenosine Monophosphate; D024981:Glycogen Phosphorylase; D025001:Glycogen Phosphorylase, Liver Form; D024982:Glycogen Phosphorylase, Muscle Form