Conformational analysis of piperazine and piperidine analogs of GBR 12909: Stochastic approach to evaluating the effects of force fields and solvent
Document Type
Article
Publication Date
1-1-2011
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. © 2010 Springer-Verlag.
Identifier
78651424713 (Scopus)
Publication Title
Journal of Molecular Modeling
External Full Text Location
https://doi.org/10.1007/s00894-010-0712-x
e-ISSN
09485023
ISSN
16102940
PubMed ID
20414792
First Page
181
Last Page
200
Issue
1
Volume
17
Grant
F31DA015555
Fund Ref
National Institutes of Health
Recommended Citation
Pandit, Deepangi; Roosma, William; Misra, Milind; Gilbert, Kathleen M.; Skawinski, William J.; and Venanzi, Carol A., "Conformational analysis of piperazine and piperidine analogs of GBR 12909: Stochastic approach to evaluating the effects of force fields and solvent" (2011). Faculty Publications. 11648.
https://digitalcommons.njit.edu/fac_pubs/11648
