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Post-doctorate fellow in search of new drugs against Hypercholesterolemia, based on specific genetic and epigenetic markers of the Brazilian population

Grant number: 19/06172-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2019
Effective date (End): March 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Fausto Feres
Grantee:Glaucio Monteiro Ferreira
Home Institution: Instituto Dante Pazzanese de Cardiologia (IDPC). Fundação Adib Jatene (FAJ). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Statins are the most commonly prescribed medications in the world. However, although considered safe, they are associated with several adverse effects, mainly those related to Myalgia and Rhabdomyolysis and other muscular symptoms related to the use of statins (SMRE), about 65% of cases of low adherence. These characteristics of statins can impair primary and secondary prevention, which consequently leads to increased morbidity, hospitalizations and mortality due to cardiovascular diseases, burdening the Unified Health System (SUS). Pharmacogenetic studies associate the risk of SMRE with profile of DNA variants. Therewith, used genetic informations for development of new drugs using strategies in silico and in vitro. The purpose of this study is using genetic information from hyperlipidemic and SMRE patients to understand molecular interactions associated with the adverse effect and to develop new structures of HMG-CoA reductase inhibitors (HMGCR) with improved efficacy and safety. For this, the variants identified by high-throughput sequencing, in a study in progress at the Dante Pazzanese Institute, with potential alteration of functional effect, support the studies of molecular interaction by Computer-Aided Drug Design (CADD), for the construction of three-dimensional models between protein structures (with and without mutations). In silico studies performed to search for new potential ligands against HMGCR based on the constructed models. Thus, new drug planning studies follow two strategies to search for these possible new bioactive compounds: Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD). Such as, molecular docking, molecular force fields (MIF's), virtual screening, enzymatic kinetic tests of HMGCR inhibition and structural optimization. This studies, search to link Molecular Biology and Medicinal Chemistry in the constructed for new drugs with against Hypercholesterolemia, contributing to the increase of therapeutic adherence, with consequent reduction of the risks of cardiovascular events and direct costs to the public health. (AU)