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.
News published in Agência FAPESP Newsletter about the scholarship: