Statins are currently the most prescribed drug against dyslipidemia. However, considered safe, statins are associated with several adverse effects, especially those related to myalgia, rhabdomyolysis and other muscle symptoms related to the use of statins (SMRE), which account for about 65% of cases of low adherence to treatment. This low adherence to treatment, consequently, leads to increased morbidity, hospitalizations and mortality due to cardiovascular diseases, which generally increases the burden on health systems. Two enzymes play a key role in the synthesis (HMG-CoA reductase, HMGCR) and metabolism (subtilisin/kexin convertase type 9, PCSK9) of cholesterol. The HMGCR gene encodes proteins that participate in the catalysis process of the rate-limiting step in cholesterol synthesis, the conversion of HMG-CoA to mevalonate. Thus, the competitive inhibition of this enzyme by statins decreases the synthesis of cholesterol 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 the reduction of plasma LDL cholesterol. For this to occur, the PCSK9 gene encodes proteins that participate in the process of cholesterol endocytosis, controlling the recycling of the LDL receptor, and accounts for up to 2% of FH cases due to the variant with gain of function, which causes greater destruction of the FH. LDL receptor and consequently an increase in plasma LDL. In this context, population genetic profiling can help in the development of new safe and effective drugs. To this end, the search for new HMGCR and PCSK9 inhibitor molecules is imminent, with the possibility of being administered orally. Thus, through molecular modeling studies using the SBVS (Structure Based Virtual Screening) strategy, to seek 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 could bring innovative perspectives for new treatments.
News published in Agência FAPESP Newsletter about the scholarship: