Identification of potential inhibitors for N-myristoyltransferase (NMT) protein of Plasmodium vivax

Abstract

Malaria is a neglected parasitic infection of global importance. It is mainly present in tropical countries and caused by a protozoa that belongs to the genus Plasmodium. The disease vectors are female Anopheles mosquitoes infected with the Plasmodium spp. According to the World Health Organization (WHO), there were 241 million malaria cases worldwide in 2020 and approximately 627 thousand malaria deaths in the same year. The increasing resistance to treatment has been a major problem since the beginning of the 21st century. New studies have been conducted to find possible drugs that can be used for the eradication of the disease. In this scenario, a protein named N-myristoyltransferase (NMT) has been studied as a potential drug target. NMT has an important role on the myristoylation of proteins and binds to the plasma membrane, contributing to the stabilization of protein-protein interactions. Thus, inhibition of NMT can lead to death of the parasite cell. Therefore, in order to predict and detect potential inhibitors against Plasmodium NMT, Computer-Aided Drug Design techniques were used in this research that involve virtual screening, molecular docking, and molecular dynamics. Three potential compounds similar to a benzofuran inhibitor were identified as stable PvNMT ligands. These compounds (EXP90, ZBC205 and ZDD968) originate from three different sources, respectively: a commercial library, a natural product library, and the FDA approved drugs dataset. These compounds may be further tested in in vitro and in vivo inhibition tests against Plasmodium vivax NMT.

Communicated by Ramaswamy H. Sarma

Keywords:

• Malaria
• NMT
• Plasmodium vivax
• virtual screening
• molecular dynamics

Acknowledgments

We would like to thank OpenEye Scientific Software for kindly providing us with its software Free Academic Licensing used in this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by FAPEMIG (Minas Gerais Research Foundation), under Grant APQ-01758-21; and CAPES (Coordination of Superior Level Staff Improvement), under Grant number 88887.664097/2022-00.