title: 3D-QSAR and 3D-QSSR studies of thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as CDK4 inhibitors by CoMFA analysis.
abstract: OBJECTIVE
  To investigate the structural basis underlying potency and selectivity of a series of novel analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones as cyclin-dependent kinase 4 (CDK4) inhibitors and to use this information for drug design strategies.
  
  
  METHODS
  Three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis (CoMFA) were conducted on a training set of 48 compounds. Partial least squares (PLS) analysis was employed. External validation was performed with a test set of 9 compounds.
  
  
  RESULTS
  The obtained 3D-QSAR model (q(2)=0.724, r(2)=0.965, r(2)pred=0.945) and 3D-QSSR model (q(2)=0.742, r(2)=0.923, r(2)pred=0.863) were robust and predictive. Contour maps with good compatibility to active binding sites provided insight into the potentially important structural features required to enhance activity and selectivity. The contour maps indicated that bulky groups at R1 position could potentially enhance CDK4 inhibitory activity, whereas bulky groups at R3 position have the opposite effect. Appropriate incorporation of bulky electropositive groups at R4 position is favorable and could improve both potency and selectivity to CDK4.
  
  
  CONCLUSIONS
  These two models provide useful information to guide drug design strategies aimed at obtaining potent and selective CDK4 inhibitors.
authors.affiliation: Key Laboratory of Applied Marine Biotechnology ministry of Education, School of Marine Sciences, Ningbo University, Ningbo 315211, China.
authors.forename: Bao-qin
authors.initials: BQ
authors.lastname: Cai
authors.affiliation: Key Laboratory of Applied Marine Biotechnology ministry of Education, School of Marine Sciences, Ningbo University, Ningbo 315211, China.
authors.forename: Hai-xiao
authors.initials: HX
authors.lastname: Jin
authors.affiliation: Key Laboratory of Applied Marine Biotechnology ministry of Education, School of Marine Sciences, Ningbo University, Ningbo 315211, China.
authors.forename: Xiao-jun
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Key Laboratory of Applied Marine Biotechnology ministry of Education, School of Marine Sciences, Ningbo University, Ningbo 315211, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhu
authors.affiliation: School of Biotechnology and Chemical Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo 315100, China.
authors.forename: Gui-xiang
authors.initials: GX
authors.lastname: Hu
mesh_terms: D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4