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dihydrofolate reductase

NOT Open Access | Discovery of novel inhibitors targeting Plasmodium knowlesi dihydrofolate reductase using molecular docking and molecular dynamics simulation

December 7, 2021 - 21:38 -- NOT Open Access
Yadav MK, Tripathi MK, Yadav S
Microb Pathog. 2021 Dec;161(Pt A):105214

Plasmodium knowlesi, recognized as the fifth Plasmodium parasite, is the least studied malaria parasite. It is a significant cause of morbidity and mortality in the South-East Asia region. Enzymes of folate synthesis, especially dihydrofolate reductase (DHFR), is a well-approved drug target in other Plasmodium species, but its role in Plasmodium knowlesi is poorly studied.

NOT Open Access | Decreased susceptibility to dihydrofolate reductase inhibitors associated with genetic polymorphisms in Ugandan Plasmodium falciparum isolates

September 1, 2021 - 16:10 -- NOT Open Access
Kreutzfeld O, Tumwebaze PK, Rosenthal PJ, et al.
J Infect Dis. 2021 Aug 30:jiab435

The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug susceptibility data for P. falciparum field isolates are limited.

NOT Open Access | Phylogenetic analysis suggests single and multiple origins of dihydrofolate reductase mutations in Plasmodium vivax

January 7, 2021 - 10:30 -- NOT Open Access
Shaukat A, Ali Q, Raud L, Wahab A, Khan TA, Rashid I, Rashid M, Hussain M, Saleem MA, Sargison ND, Chaudhry U
Acta Trop. 2021 Jan 3:105821

Pyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs in many countries. In recent years, development of pyrimethamine resistance in Plasmodium vivax has become a barrier to effective malaria control strategies. Here, we describe the use of meta-barcoded deep amplicon sequencing technology to assess the evolutionary origin of pyrimethamine resistance by analysing the flanking region of dihydrofolate reductase (dhfr) locus.

NOT Open Access | Regioisomerization of antimalarial drug WR99210 explains the inactivity of a commercial stock

October 21, 2020 - 09:24 -- NOT Open Access
Remcho TP, Guggilapu SD, Cruz P, Nardone GA, Heffernan G, O'Connor RD, Bewley CA, Wellems TE, Lane KD
Antimicrob Agents Chemother. 2020 Oct 19:AAC.01385-20

WR99210, a former antimalarial drug candidate now widely used for the selection of Plasmodium transfectants, selectively targets the parasite dihydrofolate reductase thymidine synthase bifunctional enzyme (DHFR-TS) but not human DHFR, which is not fused with TS. Accordingly, WR99210 and plasmids expressing human dhfr have become valued tools for the genetic modification of parasites in the laboratory.

NOT Open Access | Discovery of traditional Chinese medicine derived compounds as wild type and mutant Plasmodium falciparum dihydrofolate reductase inhibitors: Induced fit docking and ADME studies

August 3, 2020 - 15:34 -- NOT Open Access
Iwaloye O, Elekofehinti OO, Kikiowo B, Fadipe TM, Akinjiyan MO, Ariyo EO, Aiyeku OO, Adewumi NA
Curr Drug Discov Technol. 2020 Jul 29

In a bid to come up with effective compounds as inhibitors in antimalarial treatment, we built a library containing about 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Data-base@Taiwan. The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolate reductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to coffer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition.

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