NDLI: Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent

Content Provider	Springer Nature Link
Author	Pandit, Deepangi Roosma, William Misra, Milind Gilbert, Kathleen M. Skawinski, William J. Venanzi, Carol A.
Copyright Year	2010
Abstract	Analogs of the flexible dopamine reuptake inhibitor, GBR 12909 (1), may have potential utility in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, we carried out conformational analyses of two analogs of 1: a piperazine (2) and a related piperidine (3). Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and in implicit solvent by random search conformational analysis using the Tripos and MMFF94 force fields. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields. The force fields also differed in their descriptions of internal rotation around the C(sp 3)–O(sp 3) bond proximal to the bisphenyl moiety. Molecular orbital calculations at the HF/6-31G(d) and B3LYP/6-31G(d) levels of C–O internal rotation in model compound (5), designed to model the effect of the proximity of the bisphenyl group on C-O internal rotation, showed a broad region of low energy between −60° to 60° with minima at both −60° and 30° and a low rotational barrier at 0°, in closer agreement with the MMFF94 results than the Tripos results. Molecular mechanics calculations on model compound (6) showed that the MMFF94 force field was much more sensitive than the Tripos force field to the effects of the bisphenyl moiety on C–O internal rotation.
Starting Page	181
Ending Page	200
Page Count	20
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	17
Issue Number	1
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2010-04-23
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Conformational analysis GBR 12909 Dopamine reuptake inhibitor Dopamine transport Molecular mechanics Stochastic search Conformer population Molecular orbital Tripos force field MMFF94 force field Computer Application in Life Sciences Life Sciences Health Informatics Molecular Medicine Biomedicine general Computer Applications in Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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