title: Exploring QSAR and pharmacophore mapping of structurally diverse selective matrix metalloproteinase-2 inhibitors.
abstract: OBJECTIVE
  Matrix metalloproteinase-2 (MMP-2) is a potential target in metastases. Regression (conventional 2D QSAR) and classification (recursive partitioning (RP), Bayesian modelling) QSAR, pharmacophore mapping and 3D QSAR (comparative molecular field analysis and comparative molecular similarity analysis) were performed on 202 MMP-2 inhibitors.
  
  
  RESULTS
  Quality of the regression models was justified by internal (Q(2) ) and external (R(2) Pred ) cross-validation parameters. Stepwise regression was used to develop linear model (Q(2)  = 0.822, R(2) Pred  = 0.667). Genetic algorithm developed linear (Q(2)  = 0.845, R(2) Pred  = 0.638) and spline model (Q(2)  = 0.882, R(2) Pred  = 0.644). The RP and Bayesian models showed cross-validated area under receiver operating characteristic curve (AUCROC _ CV ) of 0.805 and 0.979 respectively. QSAR models depicted importance of descriptors like five-membered rings, fractional positively charged surface area, lipophilocity and so on. Higher molecular volume was found to be detrimental. Pharmacophore mapping was performed with two tools - Hypogen and PHASE. Both models indicated that one hydrophobic and three hydrogen bond acceptor features are essential. The Pharmacophore-aligned structures were used for CoMFA (Q(2) of 0.586 and R(2) Pred of 0.689) and CoMSIA (Q(2) of 0.673 and R(2) Pred of 0.758), results of which complied with the other analyses.
  
  
  CONCLUSIONS
  All modelling techniques were compared to each other. The current study may help in designing novel MMP-2 inhibitors.
authors.affiliation: Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Halder
authors.forename: Achintya
authors.initials: A
authors.lastname: Saha
authors.forename: Tarun
authors.initials: T
authors.lastname: Jha
mesh_terms: D001499:Bayes Theorem; D055598:Chemical Phenomena; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D054852:Small Molecule Libraries
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D054852:Small Molecule Libraries; D020778:Matrix Metalloproteinase 2
keywords: 2D QSAR; 3D QSAR; matrix-metalloproteinase-2; pharmacophore mapping; recursive partitioning