Axl Laurens Lukas Windah, Muhammad Ikhlas Abdjan, Nanik Siti Aminah, Imam Siswanto, Alfinda Novi Kristanti, Theint Su Wai, Geraldo Figo Hariyanto, Yoshiaki Takaya
Malaria is a deadly, life-threatening disease that poses significant global health challenges in terms of mortality and morbidity. The development of antimalarial drugs is essential to address this issue. This study aims to break down the inhibition molecular mechanism of (-)-ampelopsin F (AMP), one of the dimer stilbenoids isolated from Dryobalanops oblongifolia that have been previously demonstrated in our research to exhibit potent inhibition of the Plasmodium falciparum strain 3D7 (Pf3D7). A combination of computational chemistry methods, including pharmacokinetic analysis, molecular docking, and molecular dynamics simulations, was employed. This study focuses on the quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) protein to evaluate the stability and molecular behavior of AMP as an inhibitor. Based on this research, we present a novel finding that the-OH functional groups in the AMP structure may enhance solvent accessibility within the PfDHFR active site. Additionally, the prediction of binding free energy (∆Gbind) using the quantum mechanics/molecular mechanics-generalized born surface area (QM/MM-GBSA) method indicates that AMP-PfDHFR (-16.78 kcal.mol-1) exhibits better inhibitory potential compared to PC6 (pyrimethamine)-PfDHFR (-4.47 kcal.mol-1) and 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine(WRA)-PfDHFR (-12.37 kcal.mol-1). Moreover, the interaction energy analysis of each system shows that the ∆Gbind and ∆Gexp values are strongly correlated, with AMP-PfDHFR demonstrating the most stable interaction. © The Author(s) 2025.
Doctoral Program of Mathematics and Natural Sciences, Faculty of Science and Technology, Universitas Airlangga, Surabaya, 60115, Indonesia; Departement of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Surabaya, 60115, Indonesia; Department of Chemistry, Faculty of Mathematics and Natural Science Universitas Negeri Surabaya, Surabaya, 60213, Indonesia; Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga, Surabaya, 60115, Indonesia; Bioinformatic Laboratory, UCoE Research Center for BioMolecule Engineering, Universitas Airlangga, Surabaya, 60115, Indonesia; Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya, 468-8503, Japan
