Development of new drugs based on the structure of essential proteins for cholesterol synthesis and metabolism, integrating genetic studies and molecular modeling of dyslipidemic patients

• Grant number: 21/11205-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): December 01, 2021
• Effective date (End): February 29, 2024
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Mario Hiroyuki Hirata
• Grantee: Glaucio Monteiro Ferreira
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population, AP.TEM

Abstract

Statins are the most prescribed drug to treat 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 cases of poor adherence to treatment. This low adherence to treatment, consequently, leads to increased morbidity, hospitalizations and mortality due to cardiovascular diseases, which in general increases the burden on health systems. Two enzymes play a key role in the synthesis (HMG-CoA reductase, HMGCR) and in the metabolism (subtilisin/kexin type 9, PCSK9 convertase) of cholesterol. The HMGCR gene encodes proteins that participate in the catalysis process of the limiting step in cholesterol synthesis, the conversion of HMG-CoA into mevalonate. Thus, the competitive inhibition of this enzyme by statins decreases cholesterol synthesis and, through regulatory mechanisms, increases the expression of the LDL receptor, its migration on the surface of hepatocytes and, consequently, increases the uptake of circulating LDL, which results in a reduction of plasma LDL cholesterol. For this to occur, the PCSK9 gene encodes proteins that participate in the cholesterol endocytosis process, controlling the recycling of the LDL receptor, and accounts for up to 2% of HF cases due to a variant with gain of function, which causes greater destruction of the LDL receptor and consequently increased plasma LDL. In this context, the population genetic profile can help in the development of new safe and effective drugs. To this end, the search for new inhibitors of HMGCR and also of PCSK9, with the possibility of being administered orally, is imminent. Thus, through molecular modeling studies using the SBVS (Structure Based Virtual Screening) strategy, to search for molecular structures that have complementarity with HMGCR and PCSK9 in order to inhibit its mechanism. These proteins play a fundamental role in the synthesis and metabolism of cholesterol, so large-scale molecular modeling studies can evaluate compounds that can block the activity of these proteins and may bring innovative perspectives for new treatments. (AU)