In Silico Study Revealing the Inhibitory Potential of Flavonoids From Azadirachta Indica against Pf DHFR and Pf DHODH as Antimalarial Agents

Abstract Suppressing malaria remains a significant global health challenge that requires urgent attention. The emergence of resistance to several antimalarial drugs has heightened the need for novel therapeutic agents. The Neem plant ( Azadirachta indica ), which grows abundantly in Indonesia, is a promising source of prenylated flavonoids with potential antimalarial properties. This study employed in silico methods, including molecular docking and molecular dynamics simulations, to evaluate the inhibitory potential of these compounds against three key Plasmodium falciparum enzymes: wild‐type dihydrofolate reductase‐thymidylate synthase ( Pf DHFR‐TS), quadrupole mutant Pf DHFR, and dihydroorotate dehydrogenase ( Pf DHODH). The pharmacokinetic profiles of all flavonoids were also assessed. Molecular docking results revealed that the prenyl substituents enhanced binding energies and facilitated key interactions with essential amino acid residues within the target enzymes. Among the 13 flavonoids analyzed, compounds F2 and F6 exhibited notable antimalarial activity. Molecular dynamics simulations further confirmed the stability of compound F2 within the enzyme’s active site. Additionally, compound F2 demonstrated a favorable pharmacokinetic profile, complying with Lipinski’s rule of five.