REPURPOSING NATURAL PRODUCTS AGAINST PLASMODIUM KNOWLESI LACTATE DEHYDROGENASE VIA IN SILICO APPROACH FOR ANTIMALARIAL DRUG DEVELOPMENT

Abstract

Malaria cases have increased globally, which is due to the emergence of zoonotic malaria parasites that infect human, along with the existence of artemisinin-resistant parasites. Hence, there is an urgent need to find new therapeutics to counter these issues. As a vital enzyme in the glycolytic pathway that serves as the parasite's primary energy source during its intraerythrocytic stage in human, lactate dehydrogenase from Plasmodium knowlesi (Pk-LDH) can be a potential drug target. This project aims to screen for existing natural products that have progressed to preclinical or advanced drug development phases against Pk-LDH via ligand-based virtual screening (LBVS) and to evaluate the potentials of these bioactives as repurposed drugs by binding energy estimation through structure-based virtual screening (SBVS). The LBVS method, which was conducted via LiSiCA and ChemMine, are based on shape-based molecular similarity calculations to screen for analogues of the query molecules, which are lactate and pyruvate. Subsequently, PyRx simulation software were utilised for docking studies with the aid of PyMOL and PLIP software. This study discovered that Compound 7, ?-hydroxyisovaleric acid, and Compound 2, alpha-ketoisovalerate are structurally similar to compounds that directly involved in the metabolic pathways of P. knowlesi, lactate and pyruvate, with a similarity score of 0.75. Both compounds also formed strong interactions with Pk-LDH, resulting in strong binding affinities of -4.6 kcal mol^–1 and -4.3 kcal mol^–1, respectively. These findings open possibilities for using natural products in drug repurposing as anti-malarial agents.