Structure-based scoring of anthocyanins and molecular modeling of PfLDH, PfDHODH, and PfDHFR reveal novel potential P. falciparum inhibitors

Abstract

Resistance of malaria parasites to antimalarial drugs is a huge public health concern. Partial resistance of Plasmodium falciparum to artemisinin has been reported in many malaria-endemic regions. Therefore, there is a need to develop new and potent treatments which possibly target multiple genes of the parasite simultaneously. This study aimed to identify compounds with potential inhibitory interaction with P. falciparum lactate dehydrogenase (PfLDH), dihydroorotate dehydrogenase (PfDHODH), and dihydrofolate reductase (PfDHFR). Anthocyanins, a class of flavonoids were engaged to elucidate their inhibitory potential on these targets. In silico screening was performed on the selected targets and phytoligands. Following that, an additional MM-GBSA technique was used to re-score the interactions and determine the binding free energy and spontaneity of the reactions. Five compounds with outstanding binding affinities were identified for each target. The compounds demonstrated excellent binding data in comparison to the co-crystallized ligand., yielding outstanding findings, delphinidin 3,5-O-diglucoside and cyanidin 3-O-diglucoside-5-O-glucoside with −15.253 and −13.430 docking score, respectively were the compounds with the highest score. Also, the induced fit docking result shows low standard deviations. Highest bindinf affinity was recorded in PfDHFR complexes (−80.76, −67.76, −69.21, −66.06, and −67.72 kcal/mol for delphinidin 3,5-O- glucosidel, cyaniding 3-O-diglucoside-5-O-glucoside, pelargonidin 3-O-rutinoside, cyanidin 3,5-O-diglucoside and cyaniding 3-O-(6″-caffeoyl-glucoside)). Additional pharmacokinetic testing anticipated moderate profiles. The findings in this study suggest that the reported compounds can be employed in combination therapy to develop good antimalarial drugs by targeting different genes of the parasite. Hence, further exploratory analyses are recommended to validate these findings.