Grant: Discovery Grants Program - Individual

Plants are known to produce a wide array of secondary metabolites which possess valuable bioactivities. Bioprospecting of plants entails the search for economically valuable biochemical resources from the floral wealth. Bioprospecting based on ethnomedical knowledge holds out the possibility for discovering lead bioactive compounds for drug discovery program. One of the aspects of drug discovery process is the identification of small molecules with enzyme-inhibiting activities. Enzymes are essential to human life, mediating biochemical processes including metabolism, cellular signal transduction, cell cycling, and development. Malfunction in these biochemical systems often leads to disease that can be caused by the dysfunction, overexpression, or hyperactivation of the enzymes involved. An understanding of diseases at the molecular level has provided several enzyme inhibitors in clinics. For instance, lovastatin, a cholesterol-lowering agent, inhibits the activity of enzyme (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase that catalyzes the reduction of HMG-CoA to mevalonate, a key step in cholesterol biosynthesis. The proposed research involves the chemical investigation of medicinally important plants in order to identify the lead bioactive compound(s) (e.g. alkaloids, terpenoids, coumarins, steroids and flavonoids etc.) that makes them active.We have collected several plants from the Prairie Provinces of Canada and South Africa based on their ethnomedical uses by traditional healers to treat various ailments. The crude methanolic extracts of these plants exhibited various enzyme inhibitory activities including anti-acetylcholinesterase (AChE), anti-glutathioneS-transferase (GST), anti-alpha-glucosidase, anti-Plasmodium falciparum Enoyl-ACP reductase (PfENR), anti-Mycobacterium tuberculosis Enoyl-ACP reductase (MtENR) and anti-renin activities. All of these enzymes (AChE, alpha-glucosidase, GST, PfENR, MtENR and renin) are reported to be involved in the pathogenesis of Alzheimer's disease/Parkinson's disease, diabetic or improving of anti-cancer/anti-parasitic chemotherapy, malaria, TB and hypertension/cardiac problems, respectively. This research will not only validate the ethnomedical use of medicinal plants by traditional healers but also helps to identify the natural products as new candidate drugs molecule that inhibit the enzymes, involved in the pathogenesis of aforementioned health problems, as their molecular target. During this granting period, we will be carrying out four major objectives of this research program: (i) isolation and characterization of lead bioactive natural products using bioassay-directed phytochemical studies on medicinally important plants; (ii) identification of endophytic fungi as an alternative source of potent bioactive natural products; (iii) structural modifications of bioactive compounds in order to study their structure-activity relationships (SAR); and (iv) chemo-enzymatic synthesis of bioactive compounds. This interdisciplinary research integrates advanced chemical instrumentation methods (HPLC, NMR and LC-MS/GC-MS spectroscopic techniques for the purification and identification of bioactive compounds), microbial reactions, synthetic organic chemistry, computational chemistry, biochemistry and microbiology. In carrying out this research, undergraduate and graduate students will be trained as future scientists for many Canadian institutions including the biotechnological, food, chemical and pharmaceutical industries. The successful completion of this discovery grant will provide new bioactive compounds to reveal their unknown biosynthetic pathways and pharmacophores as well as to provide challenging targets to synthetic organic chemists in designing new synthetic strategies.