Molecular docking studies of potential inhibitors of acyl carrier protein and acetyl CoA Carboxylase in Plasmodium falciparum

Abstract

ABSTRACTMalaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world’s population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, 9 hit compounds were identified for each of the two enzymes from the ZincPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three (3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six (6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics (MD) simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds Zinc38980461, Zinc05378039, and Zinc15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles zinc94085628, zinc93656835, zinc94080670, zinc1774609, zinc94821232 and Zinc94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work.