A Computational Approach for Identifying Experimental or Approved Drugs That Can Be Repurposed for the Treatment of Type-2 Diabetes

Abstract

Approved and experimental drugs can be utilized for new indications as illustrated in the case study presented herein. In this case study, allopurinol (trade name Zyloprim and Aloprim) which is currently utilized for gout, was retrieved from the Drug Bank and evaluated for a new indication. Utilizing a catechin derivative as a scaffold, a derivative was designed incorporating allopurinol. This novel molecule was predicted to act as an allosteric inhibitor of fructose 1,6-bisphosphatase (FBPase), a control point for entry into the biochemical pathway gluconeogenesis. The predicted inhibition was validated with a colorimetric assay. Potential toxicity was assessed using a HepG2 MTT assay. As an inhibitor of this enzyme, the novel molecule proved to be both potent and non-toxic in cell-based assays. Once optimized and tested in vivo, the novel molecule may be potentially used as a therapeutic agent for type-2 diabetes mellitus inhibiting FBPase. This action prevents the de novo synthesis of glucose and potentially contributes to lowering blood glucose levels for patient populations that are genetically prone to chronic high blood glucose leading to insulin resistance. The computational approach to the design of the novel potential lead compound is discussed in detail and validation data presented.