Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors

Abstract

Neglected diseases are caused by infectious and parasitic agents such as viruses, bacteria, protozoa and helminths. These diseases are prevalent in low-income populations living in developing countries and are responsible for incapacitating and bringing millions to death. They are neglected because of the great medical relevance, accompanied by a few attention of the governments and pharmaceutical industries. Among these diseases we highlight trypanosomatids as Chagas disease (T. cruzi), sleeping sickness (T. brucei) and Leishmaniosis (Leishmania sp.). The chemotherapy against these diseases are oldest, present several side effects, and drug resistance has been observed. In case of Chagas disease there are only two drugs both not effective in chronic phase of the disease. This panorama suggests the urgent need in the discovery of new chemotherapy agents to promote better life condition to infected people. In general, trypanosomatids have a complex cell cycle and respond to various environmental conditions as the organism of different hosts and vectors. Sirtuins were shown to be essential for the in vitro growth of these parasites in different evolutive forms. In the case of parasites such as trypanosomatids in general, overexpression of Sir2 is related to the survival of amastigotes. Sir2 inhibitors like sirtinol showed efficacy as leishmanicidal and antichagasic in vivo assays. Thus, these evidences indicate that the Sir2 of trypanosomatids can be considered as biological targets in the search and development of new drugs. Despite the major objective of the Project is applying modern medicinal chemistry tools in search of the new chemical entities inhibitors of the parasite Sir2. In the search of the Sir2 inhibitors will be applied Structure and Ligand based drug design. For this the integration of the computational (Comparative Model, Molecular Fields interactions, pharmacophore models and virtual screening) with experimental methods (organic synthesis, protein expression and biological assays) will be performed in the identification of the potent and selective parasite Sir2 inhibitors drug candidates. (AU)