Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus.
Identifieur interne : 000759 ( Main/Exploration ); précédent : 000758; suivant : 000760Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus.
Auteurs : Ana Karina Rodrigues Abadio [Brésil] ; Erika Seki Kioshima [Brésil] ; Vincent Leroux [France] ; Natalia Florêncio Martins [Brésil] ; Bernard Maigret [France] ; Maria Sueli Soares Felipe [Brésil]Source :
- PloS one [ 1932-6203 ] ; 2015.
Abstract
The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to "nonselective" interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost-effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs.
Url:
DOI: 10.1371/journal.pone.0142926
PubMed: 26569405
Affiliations:
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The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to "nonselective" interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost-effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs.</div></front></TEI><affiliations><list><country><li>Brésil</li><li>France</li></country><region><li>Grand Est</li><li>Lorraine (région)</li><li>Mato Grosso</li></region><settlement><li>Nancy</li></settlement></list><tree><country name="Brésil"><region name="Mato Grosso"><name sortKey="Abadio, Ana Karina Rodrigues" sort="Abadio, Ana Karina Rodrigues" uniqKey="Abadio A" first="Ana Karina Rodrigues" last="Abadio">Ana Karina Rodrigues Abadio</name></region><name sortKey="Felipe, Maria Sueli Soares" sort="Felipe, Maria Sueli Soares" uniqKey="Felipe M" first="Maria Sueli Soares" last="Felipe">Maria Sueli Soares Felipe</name><name sortKey="Kioshima, Erika Seki" sort="Kioshima, Erika Seki" uniqKey="Kioshima E" first="Erika Seki" last="Kioshima">Erika Seki Kioshima</name><name sortKey="Martins, Natalia Florencio" sort="Martins, Natalia Florencio" uniqKey="Martins N" first="Natalia Florêncio" last="Martins">Natalia Florêncio Martins</name></country><country name="France"><region name="Grand Est"><name sortKey="Leroux, Vincent" sort="Leroux, Vincent" uniqKey="Leroux V" first="Vincent" last="Leroux">Vincent Leroux</name></region><name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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