Virtual Screening Identification of Nonfolate Compounds, Including a CNS Drug, as Antiparasitic Agents Inhibiting Pteridine Reductase
| Autor: | Paul A.M. Michels, Domantas Motiejunas, Véronique Hannaert, M. Paola Costi, Samuele Calò, Erika Nerini, Shreedhara Gupta, Alberto Venturelli, Stefan Henrich, Sandra Lazzari, Rosaria Luciani, Stefania Ferrari, Rebecca C. Wade, Federica Morandi |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Antiparasitic medicine.drug_class Quantitative Structure-Activity Relationship Pharmacology Small Molecule Libraries Parasitic Sensitivity Tests Drug Discovery Dihydrofolate reductase medicine Humans Benzothiazoles Leishmania Virtual screening Riluzole biology Drug discovery Chemistry Drug Synergism Fibroblasts Trypanocidal Agents Antiparasitic agent In vitro Pteridine reductase Tetrahydrofolate Dehydrogenase Pyrimethamine Drug Design biology.protein Molecular Medicine Antileishmania drug pteridine reductase CNS drug in parallel synthesis thiadiazole benzothiazole Oxidoreductases Central Nervous System Agents medicine.drug |
| Zdroj: | ResearcherID |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Folate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic drug candidates for combined therapy with dihydrofolate reductase (DHFR) inhibitors. To identify new molecules with specificity for PTR1, we carried out a virtual screening of the Available Chemicals Directory (ACD) database to select compounds that could interact with L. major PTR1 but not with human DHFR. Through two rounds of drug discovery, we successfully identified eighteen drug-like molecules with low micromolar affinities and high in vitro specificity profiles. Their efficacy against Leishmania species was studied in cultured cells of the promastigote stage, using the compounds both alone and in combination with 1 (pyrimethamine; 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine). Six compounds showed efficacy only in combination. In toxicity tests against human fibroblasts, several compounds showed low toxicity. One compound, 5c (riluzole; 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine), a known drug approved for CNS pathologies, was active in combination and is suitable for early preclinical evaluation of its potential for label extension as a PTR1 inhibitor and antiparasitic drug candidate. |
| Databáze: | OpenAIRE |
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