title: A molecular modeling study on the enantioselectivity of aryl alkyl ketone reductions by a NADPH-dependent carbonyl reductase.
abstract: Automated structural analysis of Sporobolomyces salmonicolor carbonyl reductase (SSCR) indicates that the two largest potential receptor sites are in the vicinity of the nicotinamide reductant. The largest receptor site is a scalene triangle with sides of approximately 8 A by 9 A by 13 A, which is narrow in width; one corner is surrounded by hydrophilic residues that can favorably bond with the ketone oxygen. Docking aryl alkyl ketones shows a distinct preference for binding to the largest receptor site, and for conformations that place the carbonyl oxygen of the substrate in the hydrophilic corner of the largest receptor site. Favorable docking conformations for aryl alkyl ketones fall into two low-energy ensembles. These conformational ensembles are distinguished by the positions of the substituents, presenting either the Si- or Re-face of the ketone to the nicotinamide reductant. For the ketones investigated here, there is a correspondence between the major enantiomer of the alcohol obtained from the reduction of the ketone and the conformer found to have the most stable interaction energy with the receptor site in all cases. The receptor site modeling, docking simulations, molecular dynamics, and enzyme-substrate geometry optimizations lead to a model for understanding the enantioselectivity of this NADPH-dependent carbonyl reductase.
authors.affiliation: Department of Chemistry, Center for Advanced Scientific Computing and Modeling, University of North Texas, Box 305070, Denton, TX 76203-5070, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cundari
authors.forename: Adriana
authors.initials: A
authors.lastname: Dinescu
authors.forename: Dunming
authors.initials: D
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Hua
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry*; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000596:Amino Acids / Q000032:analysis; D001487:Basidiomycota / Q000201:enzymology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011487:Protein Conformation; D055672:Static Electricity; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D007659:Ketones; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase