RESUMO
Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.
Assuntos
Anti-Infecciosos/farmacologia , Anticolesterolemiantes/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Transferases Intramoleculares/antagonistas & inibidores , Modelos Moleculares , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anticolesterolemiantes/química , Anticolesterolemiantes/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antiparasitários/química , Antiparasitários/metabolismo , Antiparasitários/farmacologia , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos/tendências , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Transferases Intramoleculares/química , Transferases Intramoleculares/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular/tendências , Conformação ProteicaRESUMO
An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter.