Antimalarial properties and molecular docking analysis of compounds from Dioscorea bulbifera L. as new antimalarial agent candidates.

Background: At present, the emergence and spread of antimalarial drug resistance has become a significant problem worldwide. There has been a challenge in searching for natural products for the development of novel antimalarial drugs. Therefore, this study aims to evaluate compounds from Dioscorea bulbifera responsible for antimalarial properties and investigate potential interactions of the compounds with Plasmodium falciparum lactate dehydrogenase (PfLDH), an essential glycolytic enzyme in the parasite's life cycle.

Methods: An in vitro study of antimalarial activity against chloroquine (CQ)-resistant Plasmodium falciparum (K1 strain) and CQ-sensitive P. falciparum (3D7 strain) was performed using the H-hypoxanthine uptake inhibition method. The cytotoxic effects of the pure compounds were tested against Vero cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The interactions of the compounds with the PfLDH active site were additionally investigated using a molecular docking method.

Results: Quercetin (6) exhibited the highest antimalarial activity against the P. falciparum K1 and 3D7 strains, with IC values of 28.47 and 50.99 μM, respectively. 2,4,3',5'-Tetrahydroxybibenzyl (9), 3,5-dimethoxyquercetin (4) and quercetin-3-O-β-D-galactopyranoside (14) also possessed antimalarial effects against these two strains of P. falciparum. Most pure compounds were nontoxic against Vero cells at a concentration of 80 μg/ml, except for compound 9, which had a cytotoxic effect with a CC value of 16.71 μM. The molecular docking results indicated that 9 exhibited the best binding affinity to the PfLDH enzyme in terms of low binding energy (- 8.91 kcal/mol) and formed strong hydrogen bond interactions with GLY29, GLY32, THR97, GLY99, PHE100, THR101 and ASN140, amino acids as active sites. In addition, 6 also possessed remarkable binding affinity (- 8.53 kcal/mol) to PfLDH by interacting with GLY29, ILE31, ASP53, ILE54, THR97 and THR101.

Conclusion: Quercetin is a major active compound responsible for the antimalarial activity of D. bulbifera and is an inhibitor of PfLDH. These findings provide more evidence to support the traditional use of D. bulbifera for malaria treatment. Structural models of its interactions at the PfLDH active site are plausibly useful for the future design of antimalarial agents.