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

C Darmanin; O El-Kabbani

doi:10.1016/s0960-894x(01)00637-0

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

Bioorg Med Chem Lett. 2001 Dec 17;11(24):3133-6. doi: 10.1016/s0960-894x(01)00637-0.

Authors

C Darmanin¹, O El-Kabbani

Affiliation

¹ Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, 3052, Victoria, Australia.

PMID: 11720859
DOI: 10.1016/s0960-894x(01)00637-0

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
L-Iditol 2-Dehydrogenase / metabolism*
Models, Molecular
Molecular Structure
Piperazines / chemistry*
Piperazines / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacology

Substances

Enzyme Inhibitors
Piperazines
Pyrimidines
2-hydroxymethyl-4-(4-(N,N-dimethylaminosulfonyl)-1-piperazino)pyrimidine
L-Iditol 2-Dehydrogenase