Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909

Anna Fiorentino, Deepangi Pandit, Kathleen M. Gilbert, Milind Misra, Rose Dios, Carol A. Venanzi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Here, Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles. The significance of the present work, the first application of SVD to the analysis of very flexible molecules, lies in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment. Over 700 conformers each of a piperazine (2) and piperidine (3) analog of 1 were studied. Analysis of the score and loading plots showed that the conformers of 2 separate into three large groups due to torsional angles on the naphthalene side of the molecule, whereas those of 3 separate into nine groups due to torsional angles on the bisphenyl side of the molecule. These differences are due to nitrogen inversion at the unprotonated piperazinyl nitrogen of 2, which results in a different ensemble of conformers than those of 3, where no inversion is possible at the corresponding piperidinyl carbon.

Original languageEnglish (US)
Pages (from-to)609-620
Number of pages12
JournalJournal of Computational Chemistry
Volume27
Issue number5
DOIs
StatePublished - Apr 15 2006

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Computational Mathematics

Keywords

  • Dopamine reuptake inhibitors
  • GBR 12909
  • Pharmacophore modeling
  • Principal component analysis
  • Singular value decomposition

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