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In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases

[Image: see text] Malaria has spread in many countries, with a 12% increase in deaths after the coronavirus disease 2019 pandemic. Malaria is one of the most concerning diseases in the Greater Mekong subregion, showing increased drug-resistant rates. Serine hydroxymethyltransferase (SHMT), a key enz...

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Autores principales: Mee-udorn, Pitchayathida, Phiwkaow, Kochakorn, Tinikul, Ruchanok, Sanachai, Kamonpan, Maenpuen, Somchart, Rungrotmongkol, Thanyada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552471/
https://www.ncbi.nlm.nih.gov/pubmed/37810721
http://dx.doi.org/10.1021/acsomega.3c01309
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author Mee-udorn, Pitchayathida
Phiwkaow, Kochakorn
Tinikul, Ruchanok
Sanachai, Kamonpan
Maenpuen, Somchart
Rungrotmongkol, Thanyada
author_facet Mee-udorn, Pitchayathida
Phiwkaow, Kochakorn
Tinikul, Ruchanok
Sanachai, Kamonpan
Maenpuen, Somchart
Rungrotmongkol, Thanyada
author_sort Mee-udorn, Pitchayathida
collection PubMed
description [Image: see text] Malaria has spread in many countries, with a 12% increase in deaths after the coronavirus disease 2019 pandemic. Malaria is one of the most concerning diseases in the Greater Mekong subregion, showing increased drug-resistant rates. Serine hydroxymethyltransferase (SHMT), a key enzyme in the deoxythymidylate synthesis pathway, has been identified as a promising antimalarial drug target due to its conserved folate binding pocket. This study used a molecular docking approach to screen 2509 US Food and Drug Administration (FDA)-approved drugs against seven Plasmodium SHMT structures. Eight compounds had significantly lower binding energies than the known SHMT inhibitors pyrazolopyran(+)-86, tetrahydrofolate, and antimalarial drugs, ranging from 4 to 10 kcal/mol. Inhibition assays testing the eight compounds against Plasmodium falciparum SHMT (PfSHMT) showed that amphotericin B was a competitive inhibitor of PfSHMT with a half-maximal inhibitory concentration (IC(50)) of 106 ± 1 μM. Therefore, a 500 ns molecular dynamics simulation of PfSHMT/PLS/amphotericin B was performed. The backbone root-mean-square deviation of the protein–ligand complex indicated the high complex stability during simulations, supported by its radius of gyration, hydrogen-bond interactions, and number of atom contacts. The appreciable binding affinity of amphotericin B for PfSHMT was indicated by their solvated interaction energy (−11.15 ± 0.09 kcal/mol) and supported by strong ligand–protein interactions (≥80% occurrences) with its essential residues (i.e., Y78, K151, N262, F266, and V365) predicted by pharmacophore modeling and per-residue decomposition free energy methods. Therefore, our findings identify a promising new PfSHMT inhibitor, albeit with less inhibitory activity, and suggest a core structure that differs from that of previous SHMT inhibitors, thus being a rational approach for novel antimalarial drug design.
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spelling pubmed-105524712023-10-06 In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases Mee-udorn, Pitchayathida Phiwkaow, Kochakorn Tinikul, Ruchanok Sanachai, Kamonpan Maenpuen, Somchart Rungrotmongkol, Thanyada ACS Omega [Image: see text] Malaria has spread in many countries, with a 12% increase in deaths after the coronavirus disease 2019 pandemic. Malaria is one of the most concerning diseases in the Greater Mekong subregion, showing increased drug-resistant rates. Serine hydroxymethyltransferase (SHMT), a key enzyme in the deoxythymidylate synthesis pathway, has been identified as a promising antimalarial drug target due to its conserved folate binding pocket. This study used a molecular docking approach to screen 2509 US Food and Drug Administration (FDA)-approved drugs against seven Plasmodium SHMT structures. Eight compounds had significantly lower binding energies than the known SHMT inhibitors pyrazolopyran(+)-86, tetrahydrofolate, and antimalarial drugs, ranging from 4 to 10 kcal/mol. Inhibition assays testing the eight compounds against Plasmodium falciparum SHMT (PfSHMT) showed that amphotericin B was a competitive inhibitor of PfSHMT with a half-maximal inhibitory concentration (IC(50)) of 106 ± 1 μM. Therefore, a 500 ns molecular dynamics simulation of PfSHMT/PLS/amphotericin B was performed. The backbone root-mean-square deviation of the protein–ligand complex indicated the high complex stability during simulations, supported by its radius of gyration, hydrogen-bond interactions, and number of atom contacts. The appreciable binding affinity of amphotericin B for PfSHMT was indicated by their solvated interaction energy (−11.15 ± 0.09 kcal/mol) and supported by strong ligand–protein interactions (≥80% occurrences) with its essential residues (i.e., Y78, K151, N262, F266, and V365) predicted by pharmacophore modeling and per-residue decomposition free energy methods. Therefore, our findings identify a promising new PfSHMT inhibitor, albeit with less inhibitory activity, and suggest a core structure that differs from that of previous SHMT inhibitors, thus being a rational approach for novel antimalarial drug design. American Chemical Society 2023-09-18 /pmc/articles/PMC10552471/ /pubmed/37810721 http://dx.doi.org/10.1021/acsomega.3c01309 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Mee-udorn, Pitchayathida
Phiwkaow, Kochakorn
Tinikul, Ruchanok
Sanachai, Kamonpan
Maenpuen, Somchart
Rungrotmongkol, Thanyada
In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title_full In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title_fullStr In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title_full_unstemmed In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title_short In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases
title_sort in silico and in vitro potential of fda-approved drugs for antimalarial drug repurposing against plasmodium serine hydroxymethyltransferases
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552471/
https://www.ncbi.nlm.nih.gov/pubmed/37810721
http://dx.doi.org/10.1021/acsomega.3c01309
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