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Combining in silico and experimental techniques to develop next generation drug like molecules for neglected diseases - leishmaniasis

Abstract

World Health Organization (WHO) defines Neglected Tropical Diseases (NTDs) as a heterogeneous group of communicable diseases prevalent in tropical and subtropical areas of 149 countries and affecting more than one billion people, bringing a high social and economic cost to developing countries. Tropical diseases such as malaria, Chagas' disease, sleep sickness and Leishmaniasis remain as some of the leading causes of morbidity and mortality worldwide. Leishmaniasis is a worldwide anthropozoonosis, being endemic in 98 countries distributed in Africa, Asia, Europe and America. It is estimated that 12 million people have already been infected with the disease and between 0.9 and 1.6 million new cases occur each year. The strategies for leishmaniasis preventive control have been ineffective in view of the increase in the number of cases and the particular appearance of cases in large urban centers in Brazil and in several regions of southern Europe. The drugs that are on the market present a series of problems, such as resistance of the parasite and induction of adverse side effects, that limit their use and mainly its effectiveness. In addition, all drugs available in Brazil and most of the countries affected are of parenteral administration, which leads to the low adhesion to the treatment and favors the emergence of resistant strains. Developing innovative molecules with high leishmanicidal potential and low cytotoxicity, expanding the arsenal of drugs that can be used to treat leishmaniasis is the main goal of the project. We will combine Cyclica's computational power with Neguebe's medicinal chemistry capabilities to rapidly bring new medicines for Leishmaniases to the market. We will use innovative in silico multi-targeted drug design (MTDD) and drug screening tools from Cyclica to design advanced lead-like molecules with desirable physichochemical, pharmacokinetic, and polypharmacological properities. We will use Neguebe's expertise in medicinal chemistry, in vitro and in vivo capabilities to validate the advanced lead-like molecules. Together, Cyclica and Negube will combine in silico and experimental assays for lead creation, prioritization of new chemical entities (NCEs) in pre-clinical setting. Cyclica and Neguebe will be responsible to select NCEs from pre-clinical trials as candidates to advance to clinical development. Neguebe will be able to develop activities related to Phase I and Phase II clinical trials, following which the clinical candidate(s) will be out-licensed to a global partner for further development. This strategy will ensure that we quickly bring to clinical the highest quality NCEs for development and partner with a recognized global partner to advance the clinical candidate to a drug. (AU)

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