SFU Royal Society of Canada: Seminar Series: "Towards Drug Candidates Against Tuberculosis and Type-2 Diabetes"

Abstract

An interdisciplinary approach that combines computer modeling, NMR spectroscopy, chemical synthesis, X-ray crystallography, enzyme kinetics, and cell-based assays for development of drug candidates is described. Two separate vignettes are presented.

The first vignette covers the investigation of new candidates against tuberculosis. The approach targets two enzymes involved in the construction of the cell wall of Mycobacterium tuberculosis. Compromising the cell wall integrity is a viable therapeutic strategy. The use of NMR spectroscopy, in conjunction with molecular dynamics calculations, are used to provide mechanistic insights of the enzymes that could guide the design of effective blockers of the enzymes. Cell-based studies are used to probe the viability of lead drug candidates against M. tuberculosis in the replicating and dormant phases.

The second vignette describes the development of a new class of molecules from a natural plant source used in traditional medicine in Sri Lanka for the treatment of Type 2 diabetes. Synthetic studies have revealed the structures of the active ingredients. Modification of the parent natural compound, salacinol, in the laboratory has also yielded a variety of analogues as candidates, some of which have subsequently been isolated from the plant source. Testing of the compounds in vitro against recombinant human maltase glucoamylase and sucrase isomaltase, critical enzymes involved in the post-amylase breakdown of carbohydrates in the small intestine, provide insight into the requirements of an effective agent. The detailed characterization of the individual enzymes now provides an understanding of the breakdown of starch and insight into certain metabolic diseases. Finally, in vivo studies in diabetic rats with selected compounds show control of plasma glucose levels, thus providing lead candidates for the control of Type 2 diabetes.