Computational design and biological evaluation of new proteasoma inhibitors, with interest in leishmaniosis and Chagas Disease

Abstract

Neglected tropical diseases are a subset of infectious diseases reaching the poorest populations, most notably Chagas disease, African Trypanosomiasis and Leishmaniasis. The investment in the discovery of new drugs for these diseases is far below what is necessary, in the specific case of Leishmaniosis, the drugs that are commercially available in addition to the high cost, have undesirable side effects and resistance of the protozoa, making the treatment ineffective. In the field of research of new hits against these protozoa, a study of proteasome inhibitor compounds of kinetoplasts was highly promising for the treatment of Chagas' disease and Leishmaniasis, according to a recent publication in the journal Nature. Motivated by the discovery of new anti-leishmania drugs, we aim to study new compounds with proteasome inhibitory potential, by synthesis and biological evaluation of molecular hybrids with leishmanicidal, trypanocidal and other analogues, as well as those obtained by virtual screening experiments in commercially available compound databases. The results will be analyzed from the molecular point of view, by docking simulations, structural homology modeling of proteasomes and QSAR-3D (Three-Dimensional Quantitative Structure-Activity Relationships), in order to create a new series of bioactive compounds that have a better activity against wild and resistant strains. The computational, synthesis and biological evaluation studies will be developed at the School of Pharmaceutical Sciences of Ribeirão Preto, under the responsibility of the researcher proponent. Carlos Tomich (FCFRP / USP) and the collaborator Prof. Dr. Cleydson B. R. dos Santos (UNIFAP-AP), doctor-oriented Suzane Q. Gomes and collaborator Prof. Flávio Emery (FCFRP / USP), and Prof. Dr. Sérgio de Albuquerque and his Post-Doctorate Carla Duque (FCFRP / USP), respectively. (AU)