Biomaterial Database

Molecular dynamics simulations of the structure of aldose reductase complexed with the inhibitor tolrestat. 1998

G Rastelli, and L Costantino

Dipartimento di Scienze Farmaceutiche, Modena, Italy. giulio@unimo.it

This study reports a molecular dynamics (MD) investigation on the structure of aldose reductase (ALR2) complexed with the potent inhibitor tolrestat. The simulations predict four different orientations of tolrestat into the ALR2 binding site; these orientations have in common a strong interaction of the anionic carboxylate with Tyr48, His110, Trp111 and NADP+, but completely differ for the orientation of the aromatic portion of the inhibitor. Interestingly, the orientation in which tolrestat gives the most attractive interaction energy with the enzyme is in full accord with the x-ray crystal structure of the complex that has been reported in the literature after this work was completed. In addition, the suggestion of more than one orientation of tolrestat during MD is in agreement with recent electrospray mass spectrometry experiments on the ALR2-tolrestat complex.

UI	MeSH Term	Description	Entries
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D009281	Naphthalenes	Two-ring crystalline hydrocarbons isolated from coal tar. They are used as intermediates in chemical synthesis, as insect repellents, fungicides, lubricants, preservatives, and, formerly, as topical antiseptics.
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D011487	Protein Conformation	The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).	Conformation, Protein,Conformations, Protein,Protein Conformations
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000449	Aldehyde Reductase	An enzyme that catalyzes reversibly the oxidation of an aldose to an alditol. It possesses broad specificity for many aldoses. EC 1.1.1.21.	Aldose Reductase,Aldose Reductase Ia,Aldose Reductase Ib,Erythrose Reductase,Xylose Reductase,Reductase Ia, Aldose,Reductase Ib, Aldose,Reductase, Aldehyde,Reductase, Aldose,Reductase, Erythrose,Reductase, Xylose