title: Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations.
abstract: 3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is generally regarded as targets for the treatment of hypercholesterolemia. HMGR inhibitors (more commonly known as statins) are discovered as plasma cholesterol lowering molecules. In this work, 120 atorvastatin analogues were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q(2)=0.558 and r(2)=0.977, and the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.582 and r(2)=0.919. Molecular docking and MD simulation explored the binding relationship of the ligand and the receptor protein. The calculation results indicated that the hydrophobic and electrostatic fields play key roles in QSAR model. After MD simulation, we found four vital residues (Lys735, Arg590, Asp690 and Asn686) and three hydrophobic regions in HMGR binding site. The calculation results show that atorvastatin analogues obtained by introduction of F atoms or gem-difluoro groups could obviously improve the inhibitory activity. The new HMGR inhibitor analogues design in this Letter had been submitted which is being currently synthesized by our laboratories.
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. Electronic address: chengliping@sit.edu.cn.
authors.forename: Liping
authors.initials: L
authors.lastname: Cheng
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Kai
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China; Key Laboratory for Advanced Materials and the Institute of Fine Chemical, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Fanhong
authors.initials: F
authors.lastname: Wu
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Minfeng
authors.initials: M
authors.lastname: Cai
mesh_terms: D000069059:Atorvastatin; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: 3D-QSAR; HMGR; Molecular dynamics simulations; Statins; gem-Difluoro