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

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.

In silico evaluation of lapachol derivatives binding to the Nsp9 of SARS-CoV-2.

SARS-CoV-2 is the etiological agent of COVID-19, which represents a global health emergency that was rapidly declared a pandemic by the World Health Organization. Currently, there is a dearth of effective targeted therapies against viruses. Natural products isolated from traditional herbal plants have had a huge impact on drug development aimed at various diseases. Lapachol is a 1,4- naphthoquinone compound that has been demonstrated to have therapeutic effects against several diseases. SARS-CoV-2 non-structural proteins (nsps) play an important role in the viral replication cycle. Nsp9 seems to play a key role in transcription of the RNA genome of SARS-CoV-2. Virtual screening by docking and molecular dynamics suggests that lapachol derivatives can interact with Nsp9 from SARS-CoV-2. Complexes of lapachol derivatives V, VI, VIII, IX, and XI with the Nsp9 RNA binding site were subjected to molecular dynamics assays, to assess the stability of the complexes via RMSD. All complexes were stable over the course of 100 ns dynamics assays. Analyses of the hydrogen bonds in the complexes showed that lapachol derivatives VI and IX demonstrated strongest binding, with a stable or increasing number of hydrogen bonds over time. Our results demonstrate that Nsp9 from SARS-CoV-2 could be an important target in prospecting for ligands with antiviral potential. In addition, we showed that lapachol derivatives are potential ligands for SARS-CoV-2 Nsp9.Communicated by Ramaswamy H. Sarma.