Reposicionamento in silico de fármacos para doenças negligenciadas com ênfase no metabolismo energético de Leishmania spp e apicoplasto de Plasmodium falciparum
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2015-02-27
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Universidade Federal de Goiás
Resumo
Leishmaniasis is a neglected tropical disease responsible for physical, economic and
social damages. Even though malaria is not classified as a neglected tropical disease, is
responsible for high morbidity and mortality, especially in African countries. Current
treatments for both diseases face several drawbacks, including the evolution of drugresistant
parasites, the high cost of major drugs and the high toxicity of others. For these
reasons, there is an urgent need to develop new drugs that minimize these downsides
and, consequently, help eradicate these diseases. To overcome these difficulties, both
academics and pharmaceutical companies are increasingly employing the so-called
“drug repositioning strategy”. Drug repositioning aims to find new applications for
drugs approved for other indications, and has proven valuable for decreasing research
costs as well as to decrease the time required to market the "new" drug. In the present
study, we used bioinformatics to identify and analyze molecular targets of the energy
metabolism of Leishmania spp and of the P. falciparum apicoplast. The energy
metabolism of Leishmania and the apicoplast metabolism have various enzymes that
can be targeted by specific drugs, leading to lower toxicity and more promising
therapies for humans. Using the TDR Targets database, we were able to identify 94
genes and 93 Leishmania energy metabolism targets. We identified 44 positive targets
in these databases, and for 11 of these targets we found drugs already approved for use
in humans. We used a similar strategy to identify antimalarial drugs that acted
specifically against the apicoplast metabolism. The GeneDB database of the P.
falciparum genome was used to compile a list of 600 proteins with apicoplast signal
peptides. Each of these proteins was treated as a potential drug target and its predicted
sequence was used to interrogate three different open access databases (DB TTD,
DrugBank and STITCH ). We identified many drugs with the potential to interact with
47 peptides allegedly involved in apicoplast biology in P. falciparum. Fifteen of these
hypothetical targets are predicted to interact with drugs are already approved for
clinical use, but were never evaluated against malaria parasites. Our results suggest that
the drugs identified here show potential activity against leishmania parasite and malaria,
but need experimental validation to confirm their effectiveness.
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SILVA, L. A. Reposicionamento in silico de fármacos para doenças negligenciadas com ênfase no metabolismo energético de Leishmania spp e apicoplasto de Plasmodium falciparum. 2015. 97 f. Tese (Doutorado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2015.