title: Modelling studies on the binding of substrate and inhibitor to the active site of human sorbitol dehydrogenase.
abstract: This study reports a molecular modelling investigation of human sorbitol dehydrogenase complexed with the substrate sorbitol and the inhibitor WAY135 706 based on the structures of human beta3 alcohol dehydrogenase, human sigma alcohol dehydrogenase and horse liver alcohol dehydrogenase. The tertiary structure of human beta3 alcohol dehydrogenase was used as a template for the construction of the model. The rms positional deviation between the main-chain atoms of the initial and final models of sorbitol dehydrogenase is 1.37 A. Similar residue interactions exist between sorbitol dehydrogenase and both sorbitol and inhibitor. Binding of sorbitol in the substrate-binding site results in interactions with Lys-294, Tyr-50, His-69, Glu-150, and NAD+ while WAY135 706 interacts with Ser-46, Lys-294 and Phe-59. The enzyme-inhibitor interactions revealed by this study will be useful in the design of more specific inhibitors.
authors.affiliation: Department of Medical Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Darmanin
authors.forename: O
authors.initials: O
authors.lastname: El-Kabbani
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013012:Sorbitol / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C106112:2-hydroxymethyl-4-(4-(N,N-dimethylaminosulfonyl)-1-piperazino)pyrimidine; D013012:Sorbitol; D007064:L-Iditol 2-Dehydrogenase; D015032:Zinc