Parthenin and Its Similar Structure as Potential Lead Inhibitors of Plasmodium vivax and Plasmodium falciparum Lactate Dehydrogenase

Abstract

Blood-borne parasite, Plasmodium vivax and Plasmodium falciparum are the most severe malaria causing organisms. Drug resistance against the present antimalarial drugs increased malaria-related morbidity and mortality. Inter-conversion of lactate and pyruvate in the glycolytic pathway requires a metabolic enzyme called lactate dehydrogenase A (LDHA). In recent years, anti-malarial therapy included several small molecules which are LDHA inhibitor in nature. Parthenin is the most active phytochemical of Parthenium hysteropohorus (Asteraceae). Maestro 9.6 software package was used for docking of parthenin like compounds (n = 85) against P. vivax, P. falciparum and the Homo sapiens lactate dehydrogenase proteins (PDB 2A92, 2A94, and 4R68 respectively) to appraise the interaction pattern of target protein and selected ligands. Docking analysis explored some ligands having excellent binding affinity against P. vivax (CID72786361, 78178433, and 11552273), P. falciparum (CID296217, 3482907, 77977597, 78178433). These lead compounds does not showed interaction with the mammalian LDH protein. Glide docking score of selected compounds and standard inhibitor of the target proteins ranged from −5.58 to −8.6 to −6.8 to −7.38 respectively. Structural investigation of selected ligands with P. vivax, P. falciparum, and mammalian LDH complexes revealed the involvement of strong hydrophobic interactions and hydrogen bonding pattern. The QikProp module of Maestro 9.6 was used to predict ADME/T (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties of the lead compounds. In conclusion, CID72786361, 78178433, 11552273 and CID296217, 3482907, 77977597, 78178433 may serve as lead LDHA inhibitor compounds to target P. vivax and P. falciparum malarial parasite respectively. Further in vitro and in vivo studies are required to assess the anti-malarial drug discovery potential of the parthenin like compounds.