Towards Targeted Antimalarial Therapies: A Review of Computational Methods in PfDHODH Inhibition

Abstract

Malaria continues to be a significant global health concern, with the risk of resurgence heightened by climate change and rising infection rates. In response, recent drug discovery efforts have identified Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) as a promising antimalarial target. Computational approaches have been instrumental in accelerating the identification and optimization of PfDHODH inhibitors, providing innovative strategies for drug design. This review examines the growing role of computational techniques in the discovery of novel PfDHODH inhibitors, emphasizing key methodologies explored in recent years. The comprehensive review analyses published studies on the development of novel PfDHODH inhibitors, focusing on molecular scaffolds and optimization strategies aimed at enhancing drug efficacy. It highlights methodologies employed in novel compound development and synthesizes key findings from each study. Additionally, it discusses the contributions of molecular docking and molecular dynamics (MD) simulations in identifying crucial binding sites. By providing insights into essential molecular features for successful PfDHODH drug design and druginhibitor interactions, this review enhances the understanding of structural insights, binding mechanisms, and computational techniques utilized in the drug discovery process.