Molecular docking, molecular dynamics simulation, and in vitro evaluation of hydroxythioxanthone derivatives as antimalarial agents

Background: In 2022, there were 247 million malaria cases spread across 84 malaria-endemic countries. One of the biggest obstacles to controlling malaria is the disease due to drug resistance. Objectives: In this study, we evaluated the antimalarial activity of hydroxythioxanthone derivatives based on the molecular docking study, and molecular dynamics (MD) simulation outcome with in vitro antimalarial evaluation. Materials and Methods: The molecular docking and MD were performed to assess the inhibition activity of hydroxythioxanthone derivatives toward Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Afterward, those compounds were evaluated the antimalarial activity against P. falciparum 3D7. Results: The docking result showed that the binding energy of those compounds was in the range of −8.05 to −9.65 kcaL/moL. Compared with A26 as a native ligand and chloroquine, compound 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) has the lowest binding energy, indicating that it had potentially more effective interactions against PfDHODH, which is remarkable. The hydrogen bonds of the 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) which were also similar to A26 took place at the amino acids His185 and Arg265. Subsequently, the 50 ns MD simulation exhibited that 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) had better stability than A26 as a native ligand and chloroquine. The in vitro evaluation of hydroxythioxanthones against P. falciparum 3D7, compound 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) gave the lowest IC50 of 6.69 µM. Conclusion: Based on in silico and in vitro evaluation, compound 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) is promising as an antimalarial drug candidate against P. falciparum 3D7.