Reposicionamento in silico de fármacos para doenças negligenciadas com ênfase no metabolismo energético de Leishmania spp e apicoplasto de Plasmodium falciparum

• Autor(a) principal: Silva, Lourival de Almeida
• Data de Publicação: 2015
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/001300000677s
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/4531
• topic: Reposicionamento de fármacos; Metabolismo energético; Leishmania spp; Apicoplasto; Plasmodium falciparum; Drug Repositioning; Energy metabolismo; Leishmania spp; Apicoplast; Plasmodium falciparum; CIENCIAS DA SAUDE

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.