Molecular docking Screening, in silico drug design and ADME prediction of 10-amidinobenzonaphthyridines as potent inhibitors of Plasmodium falciparum Lactate Dehydrogenase

Abstract

Management and control of malaria remain challenging due to the continuous emergence of drug resistant and the adaptive nature of the mosquito vector. This necessitates the continuous discovery of potent antimalaria drugs. Lactate dehydrogenase from Plasmodium falciparum (PfLDH) is an essential catalyst for the parasite’s energy production. PfLDH is a significant target in the design and discovery of antimalarial drugs because its inhibition leads to the death of the parasite. In this work, fifteen 10-amidinobenzonaphthyridine molecules active against Chloroquine-sensitive and Chloroquine-resistant strains of P. falciparum were screened through molecular docking with the view to find lead inhibitor of PfLDH. The binding affinities of the compounds ranged from -5.5 to -7.8kcal/mol. The compound with the highest binding affinity was modified and nine novel 10-amidinobenzonaphthyridines were designed. The designed compounds have better binding affinity toward the target ranging from -7.8 to -8.8kcal/mol and four of which have better binding affinities than Pyronaridine, a 10-amidinobenzonaphthyridine antimalaria drug. Furthermore, ADME properties of the designed compounds were predicted in silico and their drug-likeness investigated using Lipinski’s rule of five and Veber’s rule of two. Based on these rules, compound D1, D2, D3, D4, D5 and D8 are potential oral drug candidates. Compound D2, D3 and D8 have good binding affinities and ADME properties therefore, can be developed into potent antimalaria targeting PfLDH. The results of this work can be used to develop active antimalaria drug capable of inhibiting PfLDH.