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Virtual screening and drug repurposing: together against worm-borne diseases
* 1, 2 , 1, 3 , 4, 5 , 6, 7 , 6, 7 , 6, 7 , 6, 7 , 8, 9 , 8, 9
1  Grupo de Pesquisas Químico-Farmacêuticas da Unifesp, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Rua São Nicolau, 210, Diadema – São Paulo, Brazil
2  Federal University of Sao Paulo - UNIFESP
3  Federal University of São Paulo - UNIFESP
4  Núcleo de Pesquisas em Doenças Negligenciadas da UnG, Praça Santa Terezinha s.n, Guarulhos
5  Universidade de Guarulhos
6  Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California in San Diego, La Jolla- CA - USA
7  University of California in San Diego
8  Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro – Rio de Janeiro, Brazil
9  Federal University of Rio de Janeiro
Academic Editor: Maria Emília Sousa (registering DOI)

Worm-borne diseases cause a huge impact on human health and economics since they can also affect livestock animals. For these reasons, our research group has been employing simple rational-designed approaches to fight them. Here we present the results of combining the Virtual Screening approach and drug repurposing to find, among the drugs on the market, fast and cheap therapeutic alternatives. Starting from the top 10 pharmacophore models, validated through the ROC curve, we screened the FDA-approved drugs library to find any compound that fulfils the pharmacophore requirements. We were able to select a vitamin which was submitted to molecular dynamics simulations and in vitro experimental assays. We found out that the compound really seems to keep stable in the enzyme's active site, but it first needed to accommodate to perform a higher number of interactions inside the site. Once accommodated, the vitamin seems to be able to close the active site denying access to the original substrate. Experimental in vitro data corroborate that the vitamin is able to inhibit worm growth and induces 100% of females' death after 72 h when used at 12.5 micromolar. In vitro tests with digestive extract of the worms, prepared to predominantly measure CatB1 activity, showed that the vitamin was able to inhibit the substrate consumption closer to 10 micromolar when using the specific CatB1 substrate but when the experiment employed a non-specific substrate, the vitamin was effective only at higher doses (up to 2000 micromolar) suggesting the potential selectivity of it toward cathepsins B1.

Keywords: Helminths; Cathepsins; SmCB1; Schistosomiasis; Virtual Screening