caa a22 4500 467938873 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060401xx s 000 0 eng 10.1007/s10822-006-9046-2 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9046-2 Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs [Elektronische Daten] [Kathleen Gilbert, Carol Venanzi] Pharmacophore modeling of large, drug-like molecules, such as the dopamine reuptake inhibitor GBR 12909, is complicated by their flexibility. A comprehensive hierarchical clustering study of two GBR 12909 analogs was performed to identify representative conformers for input to three-dimensional quantitative structure-activity relationship studies of closely-related analogs. Two data sets of more than 700 conformers each produced by random search conformational analysis of a piperazine and a piperidine GBR 12909 analog were studied. Several clustering studies were carried out based on different feature sets that include the important pharmacophore elements. The distance maps, the plot of the effective number of clusters versus actual number of clusters, and the novel derived clustering statistic, percentage change in the effective number of clusters, were shown to be useful in determining the appropriate clustering level. Six clusters were chosen for each analog, each representing a different region of the torsional angle space that determines the relative orientation of the pharmacophore elements. Conformers of each cluster that are representative of these regions were identified and compared for each analog. This study illustrates the utility of using hierarchical clustering for the classification of conformers of highly flexible molecules in terms of the three-dimensional spatial orientation of key pharmacophore elements. Springer Science+Business Media B.V., 2006 Clustering nationallicence Cocaine nationallicence Conformational analysis nationallicence Dopamine reuptake inhibitor nationallicence GBR 12909 nationallicence Hierarchical nationallicence Molecular mechanics nationallicence Pharmacophore modeling nationallicence XCluster nationallicence Gilbert Kathleen Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, 07102, Newark, NJ, USA aut Venanzi Carol Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, 07102, Newark, NJ, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/4(2006-04-01), 209-225 0920-654X 20:4<209 2006 20 10822 https://doi.org/10.1007/s10822-006-9046-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9046-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gilbert Kathleen Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, 07102, Newark, NJ, USA aut NATIONALLICENCE 700 1- Venanzi Carol Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, 07102, Newark, NJ, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/4(2006-04-01), 209-225 0920-654X 20:4<209 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer