Planejamento e avaliação de novos compostos com atividade antimalárica

Abstract

Malaria continues to be a disease with major public health impacts with approximately 608,000 deaths in 2022 and limited chemotherapy. Therefore, the development of drugs with new mechanisms of action through the study of validated and/or exclusive therapeutic targets of the parasite such as Enoyl-ACP reductase (ENR) and dihydroorotate dehydrogenase (DHODH) becomes an emergency. In drug development, drug repositioning studies and the use of computational strategies can help prioritize promising molecules for biological trials. In this sense, the study proposes the use of experimental and computational data to assist in the prioritization of molecules present in drug databases (DrugBank and Sigma-Aldrich) through hierarchical virtual screening (HVS – pharmacophoric models and molecular docking) for phenotypic tests. Initially, a series of 19 thiazolidine derivatives with antimalarial activity (0.118 - 0.414 µM) were used to construct and validate pharmacophore models. After the TVH steps, ZINC61493 (Z61493) was selected based on the search parameters defined for DHODH of Plasmodium falciparum (PfDHODH) and sent for molecular dynamics (MD) studies. Subsequently, molecules from the DrugBank database were evaluated using a protocol defined in previous studies (pharmacophore model for ENR of P. falciparum inhibitors (PfENR) and molecular docking). In the tests, nitrofurantoin showed the best antiplasmodial activity profile (13.92 µM). In order to improve its permeability profile against the parasite's biological membranes, permeability studies in a lipid bilayer model through MD simulations were carried out with nitrofurantoin and its derivatives. Molecules 14, 18, 21 and Z61493 showed lower free energy values than nitrofurantoin when crossing the lipid bilayer. The feasibility of synthesizing molecules 14, 18, 21 can be evaluated in order to forward them to phenotypic tests.