Exploring the Mechanism and Product Specificity of Protein Arginine Methyltransferase 1 and Drug Discovery for Diabetes and Malaria

Abstract

In this work, three main projects are studied: (1) the mechanism and product specificity of protein arginine methyltransferase 1 (PRMT1) (2) the design and development of agonists that target peroxisome proliferator activated receptors (PPAR) as potential drugs to manage diabetes and (3) the characterization of plasmodium falciparum thioredoxin reductase (pfTrxR) inhibitors, as antimalarial drugs, using in silico techniques and biological assays. Chapter 1 is concerned with the introduction of the three proteins that were investigated in chapter 3 (PRMT1), chapter 4 (PPAR) and chapter 5 (pfTrxR). Chapter 2 is mainly concerned with the overview and theoretical background of the computational methods used in this research. Chapter 3 reports the results of the simulations carried out on PRMT1 in order to elucidate how its active site is engineered for specific product formation. The role of specific residues (Glu144, Glu153 His293 and Met48) in catalysis and controlling product specificity are discussed. Chapter 4 presents the results of a joint computational and experimental study that lead to the discovery of compound 9, a dual PPARδ/γ agonist that doesn’t elicit undesirable effects associated with full PPARγ agonists. Chapter 5 presents the results of the determination of antiplasmodial activity and binding affinity of certain compounds towards pfTrxR using combined computational and experimental approaches.