Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

Osorio, Edison; Aguilera, Concepción M.; Naranjo-Díaz, Nelson; Muskus, Carlos

doi:10.7705/biomedica.v33i3.1434

Cited by 12 publications

(7 citation statements)

References 36 publications

(35 reference statements)

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“…Susceptibility to quinazolines and miltefosine, as well as the known antifolate drugs methotrexate and pyrimethamine as positive controls, was assessed in the presence or absence of folinic acid (Figure 3). 34,35 The presence of folinic acid dramatically increased the EC 50 values of each of the quinazolines as well as the methotrexate and pyrimethamine. For example, quinazoline 23 was 6.4-fold less potent in the presence of 488 nM folinic acid than in completely deficient media.…”

Section: Resultsmentioning

confidence: 99%

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

et al. 2014

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A series of N2,N4-disubstituted quinazoline-2,4-diamines has been synthesized and tested against Leishmania donovani and L. amazonensis intracellular amastigotes. A structure–activity and structure–property relationship study was conducted in part using the Topliss operational scheme to identify new lead compounds. This study led to the identification of quinazolines with EC50 values in the single digit micromolar or high nanomolar range in addition to favorable physicochemical properties. Quinazoline 23 also displayed efficacy in a murine model of visceral leishmaniasis, reducing liver parasitemia by 37% when given by the intraperitoneal route at 15 mg kg–1 day–1 for 5 consecutive days. Their antileishmanial efficacy, ease of synthesis, and favorable physicochemical properties make the N2,N4-disubstituted quinazoline-2,4-diamine compound series a suitable platform for future development of antileishmanial agents.

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Section: Resultsmentioning

confidence: 99%

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

et al. 2014

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“…This strategy allows the expression of the recombinant protein fused to His-tag in the N-terminal domain to facilitate its purification through nickel resin affinity chromatography. The same N-terminal His-tag fusion strategy was successfully employed in the cloning, expression, and purification of Leishmania ( Vianna ) braziliensis 37 , and T. cruzi DHFR-TS 38 .…”

Section: Resultsmentioning

confidence: 99%

Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Leishmania chagasi

Teixeira

Teles

Silva

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Leishmaniasis is a tropical disease found in more than 90 countries. The drugs available to treat this disease have nonspecific action and high toxicity. In order to develop novel therapeutic alternatives to fight this ailment, pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHF-TS) have been targeted, once Leishmania is auxotrophic for folates. Although PTR1 and DHFR-TS from other protozoan parasites have been studied, their homologs in Leishmania chagasi have been poorly characterized. Hence, this work describes the optimal conditions to express the recombinant Lc PTR1 and Lc DHFR-TS enzymes, as well as balanced assay conditions for screening. Last but not the least, we show that 2,4 diaminopyrimidine derivatives are low-micromolar competitive inhibitors of both enzymes ( Lc PTR1 Ki = 1.50–2.30 µM and Lc DHFR Ki = 0.28–3.00 µM) with poor selectivity index. On the other hand, compound 5 (2,4-diaminoquinazoline derivative) is a selective Lc PTR1 inhibitor (Ki = 0.47 µM, selectivity index = 20).

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“…This bifunctional enzyme catalyzes the reduction of folate to tetrahydrofolate and the subsequent synthesis of thymidylate, an essential precursor in the synthesis of DNA [ 27 ]. For this reason, dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have been used as targets in the treatment of several diseases such as cancer [ 28 , 29 ] and infections [ 30 , 31 , 32 ]. In the case of T. cruzi DHFR-TS ( Tc DHFR-TS), several antifolates have shown inhibitory activity: trimetrexate, methotrexate and pyrimethamine [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

Juárez-Saldívar

Schroeder

Salentin

et al. 2020

IJMS

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Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

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Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

Cited by 12 publications

References 36 publications

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Leishmania chagasi

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

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Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

Cited by 12 publications

References 36 publications

Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Leishmania chagasi

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

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Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines

Antileishmanial Activity of a Series of N²,N⁴-Disubstituted Quinazoline-2,4-diamines