Selective Bias Virtual Screening for Discovery of Promising Antimalarial Candidates targeting Plasmodium N-Myristoyltransferase

Author:

Andrade Carolina1ORCID,Sousa Bruna Katiele de Paula2ORCID,Sigurdardóttir Sunniva,Bourgard Catarina,Borba Joyce,Clementino Leandro,Salazar-Alvarez Luis Carlos,Groustra Sophia,Zigweid Rachael,Khim Monique,Staker Bart,Costa Fabio,Eriksson Leif3ORCID,Sunnerhagen Per

Affiliation:

1. Federal University of Goias

2. Universidade Federal de Goiás

3. University of Gothenburg

Abstract

Abstract Malaria remains a significant public health challenge, with Plasmodium vivax being the species responsible for the most prevalent form of the disease. Given the limited therapeutic options available, the search for new antimalarials against P. vivax is urgent. This study aims to identify new inhibitors for P. vivax N-myristoyltransferase (PvNMT), an essential drug target against malaria. Through a validated virtual screening campaign, we prioritized 23 candidates for further testing. In the yeast NMT system, seven compounds exhibit a potential inhibitor phenotype. In vitro antimalarial phenotypic assays confirmed the activity of four candidates while demonstrating an absence of cytotoxicity. Enzymatic assays reveal LabMol-394 as the most promising inhibitor, displaying selectivity against the parasite and a strong correlation within the yeast system. Furthermore, molecular dynamics simulations shed some light into its binding mode. This study constitutes a substantial contribution to the exploration of a selective quinoline scaffold and provides valuable insights into the development of new antimalarial candidates.

Publisher

Research Square Platform LLC

Reference101 articles.

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3. Global epidemiology of Plasmodium vivax;Howes RE;Am. J. Trop. Med. Hyg.,2016

4. Ministério da Saúde. Secretaria de Vigilância em Saúde.Brasil. Boletim Epidemiológico. 55, (2024).

5. Plasmodium vivax liver stage development and hypnozoite persistence in human liver-chimeric mice;Mikolajczak SA;Cell Host Microbe,2015

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