Designing Molecules to Treat Ophthalmologic Diseases Caused by Sorbitol Excess

BACKGROUND: Cataracts, diabetic retinopathy, and peripheral neuropathy share a common pathophysiology: osmotic damage from sorbitol buildup. Over a lifetime, metabolism of glucose results in sorbitol buildup in certain tissues (lens, retina, Schwann cells) that have limited amounts of the sorbitol dehydrogenase enzyme to degrade it into fructose. Current state-of-the-art techniques to treat this pathophysiology target the ultimate effects (i.e. surgical replacement of cataracts with artificial lenses) or prevent the initial glucose excess (i.e. anti-diabetic medications). Approaches to targeting the sorbitol pathway itself were attempted when the pathophysiology was first elucidated decades ago. With advancements in molecular design, novel drugs may play a promising role in new therapeutic avenues. METHODS: Protein Data Banks (PDB) in Europe’s Chemical Components and Research Collaboratory for Structural Bioinformatics (RCSB) were utilized to identify the ligand D-allitol alone and contained in ABC transporter solute binding protein from Agrobacterium vitis. Using PyMOL, computational modeling was utilized to iteratively generate mutations in residue-ligand interactions to identify structures with improved stabilization of sorbitol in the binding pocket. RESULTS: We found multiple proteins that have potential to sequester sorbitol. We demonstrate a thermodynamically favorable (highly negative) Gibbs free energy for these molecules. Our results indicate that molecules likely do exist that can treat diabetic eye diseases via a mechanism of action targeting sorbitol. DISCUSSION: Computational modeling is an efficient approach for identifying potentially successful molecules, but validation in animal models needs to be done. Additionally, so far, we have only studied sorbitol-sequestering molecules that are protein-based (biologics). Biologics in general pose greater pharmacologic problems including decreased molecular stability and the requirement for more invasive routes of administration (i.e. bevacizumab- intravitreal or intravenous injection). As such, small molecule agents are highly favored if they can produce the same pharmacodynamic effect. Future research may focus on a targeted drug design to create small molecules that can sequester sorbitol. Possible mechanisms of action for these small molecules include inhibition of the metabolic pathway’s key enzymes (aldose reductase and sorbitol dehydrogenase) and molecular efflux of the reaction products (sorbitol and fructose).