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PfDHODH

NOT Open Access | High-throughput virtual screening approach involving pharmacophore mapping, ADME filtering, molecular docking and MM-GBSA to identify new dual target inhibitors of PfDHODH and PfCytbc1 complex to combat drug resistant malaria

September 8, 2021 - 16:01 -- NOT Open Access
Author(s): 
Rawat R, Verma SM
Reference: 
J Biomol Struct Dyn. 2021 Sep;39(14):5148-5159

Emerging cases of drug resistance against Artemisinin combination therapies which are the current and the last line of defense against malaria makes the situation very alarming. Due to the liability of single-target drugs to be more prone to drug resistance, the trend of development of dual or multi-target inhibitors is emerging. Recently, a malaria box molecule, MMV007571 which is a well known new permeability pathways inhibitor was investigated to be also multi-targeting Plasmodium falciparum dihydroorotate dehydrogenase and cytochrome bc1 complex.

Exploring natural microbial resources for the discovery of anti-malarial compounds

August 10, 2021 - 18:00 -- Open Access
Author(s): 
Waluyo D, Prabandari EE, Nozaki T, et al.
Reference: 
Parasitol Int. 2021 Aug 4:102432

Microorganisms in nature are highly diverse biological resources, which can be explored for drug discovery. Some countries including Brazil, Columbia, Indonesia, China, and Mexico, which are blessed with geographical uniqueness with diverse climates display remarkable megabiodiversity, potentially provide microorganismal resources for such exploitation.

NOT Open Access | Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors

January 6, 2021 - 13:03 -- NOT Open Access
Author(s): 
Silveira FF, de Souza JO, Pinheiro LCS, et al.
Reference: 
Eur J Med Chem. 2021 Jan 1;209:112941

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030-0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08-1.3 μM) and did not show significant inhibition against the HsDHODH homologue (0-30% at 50 μM).

NOT Open Access | High-throughput virtual screening approach involving pharmacophore mapping, ADME filtering, molecular docking and MM-GBSA to identify new dual target inhibitors of PfDHODH and PfCytbc1 complex to combat drug resistant malaria

June 26, 2020 - 12:03 -- NOT Open Access
Author(s): 
Rawat R, Verma SM
Reference: 
J Biomol Struct Dyn. 2020 Jun 24:1-12

Emerging cases of drug resistance against Artemisinin combination therapies which are the current and the last line of defense against malaria makes the situation very alarming. Due to the liability of single-target drugs to be more prone to drug resistance, the trend of development of dual or multi-target inhibitors is emerging. Recently, a malaria box molecule, MMV007571 which is a well known new permeability pathways inhibitor was investigated to be also multi-targeting Plasmodium falciparum dihydroorotate dehydrogenase and cytochrome bc1 complex. The aspiration behind this study was to use the information of its pharmacophoric features essential for binding as two of its new targets.

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