Repurposing FDA‐approved drugs to target malaria through inhibition of dihydrofolate reductase in the folate biosynthesis pathway: A prospective approach

Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that regulates the biosynthesis of tetrahydrofolate among various species of Plasmodium parasite. It is a validated target of the antifolate drug pyrimethamine (Pyr) in Plasmodium falciparum (Pf), but its clinical efficacy has been hampered due t...

Full description

Saved in:
Bibliographic Details
Published in:Journal of cellular biochemistry 2024-03, Vol.125 (3), p.e30533-n/a
Main Authors: Verma, Kanika, Chaturvedi, Rini, Lahariya, Ayush K., Verma, Anil K., Schneider, Kristan A., Anvikar, Anup R., Bharti, Praveen K.
Format: Article
Language:English
Subjects:
Biosynthesis
Dihydrofolate reductase
dihydrofolate reductase (DHFR)
Drug development
Drug resistance
Drugs
Duloxetine
Effectiveness
Folic acid
Guanethidine
Malaria
molecular docking
molecular simulation
Parasites
Pyrimethamine
Reductases
repurposing
Solvation
Tetrahydrofolic acid
Vector-borne diseases
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that regulates the biosynthesis of tetrahydrofolate among various species of Plasmodium parasite. It is a validated target of the antifolate drug pyrimethamine (Pyr) in Plasmodium falciparum (Pf), but its clinical efficacy has been hampered due to the emergence of drug resistance. This has made the attempt to screen Food & Drug Administration‐approved drugs against wild‐ and mutant PfDHFR by employing an in‐silico pipeline to identify potent candidates. The current study has followed a virtual screening approach for identifying potential DHFR inhibitors from DrugBank database, based on a structure similarity search of candidates, followed by absorption, distribution, metabolism, and excretion estimation. The screened drugs were subjected to various parameters like docking, molecular mechanics with generalized born and surface area solvation calculations, and molecular simulations. We have thus identified two potential drug candidates, duloxetine and guanethidine, which can be repurposed to be tested for their efficacy against wild type and drug resistant falciparum malaria.
ISSN:0730-2312
1097-4644
1097-4644
DOI:10.1002/jcb.30533