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Novel HMG-CoA reductase inhibitors development by integrating dyslipidemic patients' genetic studies and molecular modelling

Grant number: 19/24112-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): April 23, 2020
Effective date (End): March 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Fausto Feres
Grantee:Glaucio Monteiro Ferreira
Supervisor abroad: Antti Poso
Home Institution: Instituto Dante Pazzanese de Cardiologia (IDPC). Fundação Adib Jatene (FAJ). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Research place: Eberhard Karls Universität Tübingen, Germany  
Associated to the scholarship:19/06172-4 - Post-doctorate fellow in search of new drugs against Hypercholesterolemia, based on specific genetic and epigenetic markers of the Brazilian population, BP.PD

Abstract

Statins are currently the most prescribed drug against dyslipidemia. However, considered safe, statins are associated with several adverse effects, especially those related to myalgias, rhabdomyolysis and other muscular symptoms related to the use of statins (SMRE), which account for about 65% of low treatment adherence cases. This low treatment adherence, consequently, leads to increased morbidity, hospitalizations and mortality, due to cardiovascular diseases, which overall increases the burden on the health care systems. Pharmacogenetic studies can associate these adverse effects with a DNA variant profile. In this context, population genetic profiling can help in the development of new safe and effective drugs. The purpose of this study is to use genetic information from hyperlipidemic patients to understand molecular interactions associated with the adverse effect and to develop new HMG-CoA reductase inhibitors (HMGR) with improved efficacy and safety. For this, the genetic variants identified by high-throughput sequencing, in a group progress study, with potential alteration of functional effect, will support Computer-aided drug design (CADD) studies, using in silico tools to generate structural models of HMGCR. Thus, the results will guide the search for new small molecules, using tools such as molecular docking, molecular dynamics, MIFs (Molecular Interactions Fields), virtual screening studies, followed by enzymatic kinetic tests for HMGR inhibition, and structural optimization. The present study, to the best of our knowledge, is a pioneer in this approach, which interconnects molecular biology and medicinal chemistry and aims to contribute to increased therapeutic adherence to statins, with a consequent reduction in the risk of cardiovascular events and direct public health costs.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DOS SANTOS, BENEDITO MATHEUS; FERREIRA, GLAUCIO MONTEIRO; TAVARES, MAURICIO TEMOTHEO; DE BONA, JULIO CESAR; HIRATA, MARIO HIROYUKI; DE PAULA, VANDERLUCIA FONSECA; SATURNINO, KLAUS CASARO; SOARES, ANDREIMAR MARTINS; MENDES, MIRIAN MACHADO. Antiophidic activity of the secondary metabolite lupeol isolated from Zanthoxylum monogynum. Toxicon, v. 193, p. 38-47, APR 15 2021. Web of Science Citations: 0.
SOUZA, CAMILA O.; TEIXEIRA, ALEXANDRE A. S.; BIONDO, LUANA AMORIM; SILVEIRA, LOREANA SANCHES; DE SOUZA BREDA, CRISTIANE N.; BRAGA, TARCIO T.; CAMARA, NIELS O. S.; BELCHIOR, THIAGO; FESTUCCIA, WILLIAM T.; DINIZ, TIEGO A.; FERREIRA, GLAUCIO MONTEIRO; HIRATA, MARIO HIROYUKI; CHAVES-FILHO, ADRIANO B.; YOSHINAGA, MARCOS Y.; MIYAMOTO, SAYURI; CALDER, PHILIP C.; SETHI, JASWINDER K.; ROSA NETO, JOSE C. Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-gamma-independent M2a polarization of myeloid cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1865, n. 10 OCT 2020. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.