Biomedical subjects

C Darmanin

Publications and source records attributed to C Darmanin.

4 recordsLinked to original sources

PubMed2004

Aldose reductase structures: implications for mechanism and inhibition.

During chronic hyperglycaemia, elevated vascular glucose level causes increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications. Inhibitors of aldose reductase (ARIs) have been widely investigated as potential therapeutic agents, but to date only epalrestat is successfully marketed for treatment of diabetic neuropathy, in Japan. Promising compounds during in vitro studies or in trials with animal models have failed to proceed beyond clinical trials and to everyday use, due to a lack of efficacy or adverse side effects attributed to lack of inhibitor specificity and likely inhibition of the related aldehyde reductase (ALR1). Knowledge of the catalytic mechanism and structures of the current inhibitors complexed with ALR2 are means by which more specific and tightly bound inhibitors can be discovered. This review will provide an overview of the proposed catalytic mechanism and the current state of structure-based drug design.

Aldehyde Reductase↗

PubMed2004

Sorbitol dehydrogenase: structure, function and ligand design.

Sorbitol dehydrogenase (SDH), a member of the medium-chain dehydrogenase/reductase protein family and the second enzyme of the polyol pathway of glucose metabolism, converts sorbitol to fructose strictly using NAD(+) as coenzyme. SDH is expressed almost ubiquitously in all mammalian tissues. The enzyme has attracted considerable interest due to its implication in the development of diabetic complications and thus its tertiary structure may facilitate the development of drugs for the treatment of diabetes sufferers. Modelling studies suggest that SDH is structurally homologous to mammalian alcohol dehydrogenase with respect to conserved zinc binding motif and a hydrophobic substrate-binding pocket. Recently, the three-dimensional (3-D) structure of a mammalian SDH was solved, and it was found that while the overall 3-D structures of SDH and alcohol dehydrogenase are similar, the zinc coordination in the active sites of the two enzymes is different. The available structural and biochemical information of SDH are currently being utilized in a structure-based approach to develop drugs for the treatment or prevention of the complications of diabetes. This review provides an overview of the recent advances in the structure, function and drug development fields of sorbitol dehydrogenase.

Amino Acid Sequence↗

PubMed2001

Modelling studies of the active site of human sorbitol dehydrogenase: an approach to structure-based inhibitor design of the enzyme.

The program GRID was used to design novel potential inhibitors of human sorbitol dehydrogenase based on a model of the holoenzyme in complex with the inhibitor WAY135 706. Replacement of the methyl hydroxyl group of the inhibitor with methyl phosphate and methyl carboxylate functional groups increased the net binding energy of the complex by 2.0- and 1.7-fold, respectively. This study may be useful in the development of potent and more specific inhibitors of the enzyme.

Binding Sites↗

PubMed2000

Modelling studies on the binding of substrate and inhibitor to the active site of human sorbitol dehydrogenase.

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.

Amino Acid Sequence↗