Computational analysis of binding between malarial dihydrofolate reductases and anti-folates
Abstract Background Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutation...
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ftdoajarticles:oai:doaj.org/article:b4a21d3dd74e47f5b4c7c4e1350507da 2023-05-15T15:15:38+02:00 Computational analysis of binding between malarial dihydrofolate reductases and anti-folates White Nicholas J Day Nicholas PJ Songtawee Napat Theppabutr Sasikrit Choowongkomon Kiattawee Woodrow Charles J Imwong Mallika 2010-03-01T00:00:00Z https://doi.org/10.1186/1475-2875-9-65 https://doaj.org/article/b4a21d3dd74e47f5b4c7c4e1350507da EN eng BMC http://www.malariajournal.com/content/9/1/65 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-9-65 1475-2875 https://doaj.org/article/b4a21d3dd74e47f5b4c7c4e1350507da Malaria Journal, Vol 9, Iss 1, p 65 (2010) Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2010 ftdoajarticles https://doi.org/10.1186/1475-2875-9-65 2022-12-30T21:42:01Z Abstract Background Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutations can be found in the DHFR gene in isolates of Plasmodium vivax (PvDHFR) although anti-folates have not been widely used for the treatment of this infection. Here the interactions between DHFR inhibitors and modelled structures of the DHFR enzymes of Plasmodium malariae (PmDHFR) and Plasmodium ovale (PoDHFR) are described, along with an investigation of the effect of recently reported mutations within PmDHFR. Methods DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics. Results Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding. Conclusions Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax . Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 9 1 65 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 White Nicholas J Day Nicholas PJ Songtawee Napat Theppabutr Sasikrit Choowongkomon Kiattawee Woodrow Charles J Imwong Mallika Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutations can be found in the DHFR gene in isolates of Plasmodium vivax (PvDHFR) although anti-folates have not been widely used for the treatment of this infection. Here the interactions between DHFR inhibitors and modelled structures of the DHFR enzymes of Plasmodium malariae (PmDHFR) and Plasmodium ovale (PoDHFR) are described, along with an investigation of the effect of recently reported mutations within PmDHFR. Methods DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics. Results Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding. Conclusions Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax . |
format |
Article in Journal/Newspaper |
author |
White Nicholas J Day Nicholas PJ Songtawee Napat Theppabutr Sasikrit Choowongkomon Kiattawee Woodrow Charles J Imwong Mallika |
author_facet |
White Nicholas J Day Nicholas PJ Songtawee Napat Theppabutr Sasikrit Choowongkomon Kiattawee Woodrow Charles J Imwong Mallika |
author_sort |
White Nicholas J |
title |
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
title_short |
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
title_full |
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
title_fullStr |
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
title_full_unstemmed |
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
title_sort |
computational analysis of binding between malarial dihydrofolate reductases and anti-folates |
publisher |
BMC |
publishDate |
2010 |
url |
https://doi.org/10.1186/1475-2875-9-65 https://doaj.org/article/b4a21d3dd74e47f5b4c7c4e1350507da |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 9, Iss 1, p 65 (2010) |
op_relation |
http://www.malariajournal.com/content/9/1/65 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-9-65 1475-2875 https://doaj.org/article/b4a21d3dd74e47f5b4c7c4e1350507da |
op_doi |
https://doi.org/10.1186/1475-2875-9-65 |
container_title |
Malaria Journal |
container_volume |
9 |
container_issue |
1 |
container_start_page |
65 |
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1766346001006723072 |