Aldose reductase as a target for drug design: molecular modeling calculations on the binding of acyclic sugar substrates to the enzyme.

In an attempt to obtain a picture of the binding conformation of aldehyde substrates to human aldose reductase (hAR), modeling calculations have been performed on the binding of three substrates, D-xylose, L-xylose, and D-lyxose, to wild-type human aldose reductase and two of its site-directed mutants. It was found that the average geometry of D-xylose in the active site of wild-type aldose reductase is characterized by strong hydrogen bonds involving the reactive carbonyl oxygen of the substrate and both Tyr48 and His110. The calculations also suggest the importance of Trp111 in the binding of 2'-hydroxyl-containing aldehyde substrates. A good correlation between calculated interaction enthalpies and experimental log(Km) or log(kcat/Km) values was obtained when His110 was modeled with its N epsilon 2 atom protonated and N delta 1 unprotonated. No correlation was found for the other two configurations of His110. On the basis of comparisons of the calculated substrate binding conformations for the three possible His110 configurations, and on the correlations between measured log(Km) or log(kcat/Km) and calculated parameters, it is proposed that His110 is neutral and protonated at N epsilon 2 when an aldehyde substrate is bound to the hAR/NADPH complex. A chain of three hydrogen-bonded water molecules has been identified in all available crystal structures and is located in an enzyme channel which links the N delta 1 atom of His110 to the solvent-accessible surface of the enzyme. A possible role of this channel in the mechanism of catalysis of aldose reductase is suggested.

1-(2,3-Dideoxy-erythro-beta-D-hexopyranosyl)cytosine: an example of the conformational and stacking properties of pyranosyl pyrimidine nucleosides. A crystallographic and computational approach.

C10H15N3O4, Mr = 241.25, orthorhombic, P2(1)2(1)2(1), a = 7.4013 (4), b = 8.7563 (5), c = 17.392 (1) A, V = 1127.1 (1) A3, Z = 4, Dm = 1.42, Dx = 1.422 Mg m-3, Ni-filtered Cu K alpha radiation, lambda = 1.54178 A, mu = 0.895 mm-1, F(000) = 512, T = 293 K, final R = 0.044 for 1024 unique observed [F greater than or equal to 6 sigma (F)] reflections. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. In order to assess the possible use of pyranosyl-modified pyrimidine nucleosides in the design of new synthetic oligonucleotides, the conformational and packing properties of 13 structures were examined. From this study, it becomes clear that the pyrimidine-base geometry is independent of the sugar ring type (furanosyl- or pyranosyl-like). The bases are always positioned in an equatorial orientation on the pyranoside sugar, which means that the sugar adopts a 4C1 conformation in alpha- and 4C1 in beta-enantiomers. As a result of the anomeric effect the O5'-C1' bond length is 0.020 (4) A shorter than the C5'-O5' distance (C1' is the anomeric C atom). The O5'-C1'-N1-C2 torsion angle chi in the 13 nucleosides is centered around 244 (8) degrees and varies from 196.4 (3) to 287.0 (2) degrees. Molecular-mechanics calculations on uncharged pyranosyl nucleosides are found to be less accurate compared with semi-empirical quantum-chemical methods or molecular-mechanics calculations on charged molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure of the neuroleptic drug 4-amino-N-1-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2- methoxybenzamide (amisulpride).

C17H27N3O4S, Mr = 369.48, monoclinic, P2(1)/c, a = 13.333 (7), b = 7.946 (4), c = 17.550 (10) A, beta = 96.99 (4) degrees, V = 1845 (2) A3, Z = 4, Dm = 1.33, Dx = 1.330 Mg m-3, graphite-monochromated Cu K alpha radiation, lambda = 1.54178 A, mu = 1.744 mm-1, F(000) = 792, T = 293 K. Final R = 0.038 for 2405 unique observed reflections. The folded conformation of the molecule with the least-squares planes of the aromatic and the pyrrolidine rings almost perpendicular is essentially determined by intra- and intermolecular hydrogen bonds. In this way, two pseudorings are formed, one linking the amide H with the methoxy O, and a second one involving the 4-amino H and a sulfonyl O. An intermolecular hydrogen bond forces the planar amide group some 28 degrees out of the plane of the aromatic ring.