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

Document Type

Article

Publication Date

4-15-2006

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. © 2006 Wiley Periodicals, Inc.

Identifier

33645308242 (Scopus)

Publication Title

Journal of Computational Chemistry

External Full Text Location

https://doi.org/10.1002/jcc.20371

e-ISSN

1096987X

ISSN

01928651

PubMed ID

16470669

First Page

609

Last Page

620

Issue

5

Volume

27

Grant

R15DA018153

Fund Ref

National Institute on Drug Abuse

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