Repurposing FDA-approved drugs to target malaria through inhibition of dihydrofolate reductase in the folate biosynthesis pathway: A prospective approach.
J Cell Biochem
; 125(3): e30533, 2024 03.
Article
in En
| MEDLINE
| ID: mdl-38345373
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Folic Acid Antagonists
/
Malaria
/
Antimalarials
Limits:
Humans
Language:
En
Journal:
J Cell Biochem
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: