AUTHOR=Enninful Kweku S. , Kwofie Samuel K. , Tetteh-Tsifoanya Mark , Lamptey Amanda N. L. , Djameh Georgina , Nyarko Samuel , Ghansah Anita , Wilson Michael D. 

TITLE=Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.868529

DOI=10.3389/fcimb.2022.868529

ISSN=2235-2988

ABSTRACT=Recent reports of resistance to artemisinin-based combination drugs necessitate the need to discover novel antimalarial compounds. The present study was aimed at identifying novel antimalarial compounds from natural product libraries using computational methods. Plasmodium falciparum is highly dependent on the pyrimidine biosynthetic pathway, a de novo pathway responsible for the production of pyrimidines and the parasite lacks the pyrimidine salvage enzymes. The P. falciparum thymidylate monophosphate kinase (PfTMPK) is an important protein necessary for rapid DNA replication however, due to its broad substrate specificity the protein is distinguished from its homologues making it a suitable drug target. Compounds from AfroDB, a database of natural products originating from Africa were screened virtually against PfTMPK after filtering the compounds for ADMET acceptable compounds with the FAF Drug4. Thirteen hits with lower binding energies than thymidine monophosphate were selected after docking. Among the thirteen compounds, ZINC13374323 and ZINC13365918 with binding energies of -9.4 and -8.9 Kcal/mol were selected as plausible lead compounds because they exhibited structural properties that ensures proper binding at the active site and inhibitory effect against PfTMPK. ZINC13374323 (also called Aurantiamide acetate) is known to exhibit anti-inflammatory and antiviral activity, and ZINC13365918 exhibits antileishmanial activity. Furthermore, Aurantiamide acetate is a constituent of Artemisia annua, the herb from which artemisinin was derived is commercially available. The compound also shares interactions with several residues with a potent thymidine analogue inhibitor of PfTMPK. The anti-plasmodia activity of Aurantiamide acetate was evaluated in vitro and the mean IC50 was 69.33μM when synchronized P. falciparum 3D7 culture was used compared to IC50 > 100μM with asynchronized culture. The significance of our findings within the context of malaria treatment strategies and challenges is discussed.