Molecular Design Of Novel Fluorinated Hydroxyl-methyl Glutaryl Goenzyme A Teductase Inhibitors

Hydroxymethyl-coenzyme A reductase (HMGR) is a protease which is highly enriched in human, insects and other organisms in vivo, it is not only the cholesterol synthesis route in human body of self-limiting enzyme in the first step, but also the important hormones of insects-Juvenile hormore (JH) biosynthesis of a significant rate-limiting enzyme. Therefore, the inhibitor is the best drug (statins) for treating cardiovascular disease, and that it is a potential nevol pesticide. In this letter,120 atorvastatin analogues were studied using a combination of molecular modeling technoques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. We established the 3D-QSAR models of the HMGR enzyme inhibitory activity, the cholesterol synthesis in liver cell inhibitory activity and the drug selectivity, respectively. The optimal correlation between the results of comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) models are:q2= 0.558, r2= 0.977 and q2= 0.582. r2= 0.919; q2= 0.659, r2= 0.980 and q2= 0.665, r2= 0.971; q2= 0.618, r2= 0.979 and q2= 0.56, r2= 0.971. According to the contour map analyses of five force fileds, the corresponding position of fatty chain of the HMGR inhibitor structure introduced the large electronegativity atoms or groups could improved the inhibitory activity, such as the fluorine-containing groups. Furthermore, Accoding to the molecular docking results, three hydrophobic cores formed by the aromatic rings of the atorvastatin analogues and the hydrophobic amino acid residues in right site of HMGR binding pocket developed interaction relationship. The MD simulation study further validates the results of molecular docking, on the basis of MD simulation stable conformation, and proposed the "scorpion" model.Afterwards, combined the ho mo logy modeling, molecular docking, MD simulation and 3D-QSAR et al simulation methods to study the manduca sexta HMGR and our lab group synthesized and tested in vivo inhibition of insect JH biosynthesis of gem-difluoro statins. The results shown:the human HMGR crystal structure could model the insect HMGR of 3D structures, the results of molecular docking analysis indicated the different binding mode of statins between human HMGR and insect HMGR. Compared to the IC50 valuesof inhibitory HMGR activity and the ΔGbindina ofMD simulation evidenced the HMGR as a nevol pesticide target. The results are not only to provide guidance on the design of a high activity, selectivity and safety of statins, but also for the development of a novel green pesticide give particular theoretical guidance.