CoMFA study of piperidine analogues of cocaine at the dopamine transporter: Exploring the binding mode of the 3α-substituent of the piperidine ring using pharmacophore-based flexible alignment

Hongbin Yuan, Alan P. Kozikowski, Pavel A. Petukhov

Research output: Contribution to journalArticle

Abstract

A 3D-QSAR CoMFA study of piperidine-based analogues of cocaine with flexible 3α-substituents is described. A series of pharmacophore models were generated based on three representative compounds 1p, 2i, and 3c using the Genetic Algorithm Similarity Program (GASP) method. The flexible superposition of all studied compounds was performed for each pharmacophore model using the FlexS algorithm and the three-dimensional structure of 2i as a template. All sets of the overlaid structures with the top-ranked conformers were used for CoMFA modeling. Two best initial CoMFA models were selected and further optimized by identifying the best-fitting conformer of each compound. Compared with the initial models, the conventional correlation coefficients r2 for the optimized models 1 and 2 were improved from 0.90 and 0.837 to 0.997 and 0.993, respectively. The leave-one-out cross-validated coefficients q 2 for the optimized models 1 and 2 were improved from 0.515 and 0.296 to 0.828 and 0.849, respectively. The results of the two CoMFA models suggest that both steric and electrostatic interactions play important roles in the binding of the 3γ-substituents of the piperidine-based analogues of cocaine. The contributions from steric and electrostatic fields for model 1 were 0.621 and 0.379, respectively. The contributions from steric and electrostatic fields for model 2 were 0.493 and 0.507, respectively. The two highly predictive CoMFA models indicate that the 3α-substituent has two possible binding modes at the DAT. The CoMFA contour maps provide a visual representation of prospective binding modes of the 3α-substituent of the piperidine-based analogues of cocaine and can be used to design novel DAT inhibitors that may be useful for the treatment of cocaine abuse and certain neurological disorders.

Original languageEnglish (US)
Pages (from-to)6137-6143
Number of pages7
JournalJournal of Medicinal Chemistry
Volume47
Issue number25
DOIs
StatePublished - Dec 2 2004
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Static Electricity
Cocaine
Cocaine-Related Disorders
Quantitative Structure-Activity Relationship
Nervous System Diseases
Electric fields
piperidine
Coulomb interactions
Genetic algorithms

ASJC Scopus subject areas

  • Organic Chemistry

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CoMFA study of piperidine analogues of cocaine at the dopamine transporter : Exploring the binding mode of the 3α-substituent of the piperidine ring using pharmacophore-based flexible alignment. / Yuan, Hongbin; Kozikowski, Alan P.; Petukhov, Pavel A.

In: Journal of Medicinal Chemistry, Vol. 47, No. 25, 02.12.2004, p. 6137-6143.

Research output: Contribution to journalArticle

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abstract = "A 3D-QSAR CoMFA study of piperidine-based analogues of cocaine with flexible 3α-substituents is described. A series of pharmacophore models were generated based on three representative compounds 1p, 2i, and 3c using the Genetic Algorithm Similarity Program (GASP) method. The flexible superposition of all studied compounds was performed for each pharmacophore model using the FlexS algorithm and the three-dimensional structure of 2i as a template. All sets of the overlaid structures with the top-ranked conformers were used for CoMFA modeling. Two best initial CoMFA models were selected and further optimized by identifying the best-fitting conformer of each compound. Compared with the initial models, the conventional correlation coefficients r2 for the optimized models 1 and 2 were improved from 0.90 and 0.837 to 0.997 and 0.993, respectively. The leave-one-out cross-validated coefficients q 2 for the optimized models 1 and 2 were improved from 0.515 and 0.296 to 0.828 and 0.849, respectively. The results of the two CoMFA models suggest that both steric and electrostatic interactions play important roles in the binding of the 3γ-substituents of the piperidine-based analogues of cocaine. The contributions from steric and electrostatic fields for model 1 were 0.621 and 0.379, respectively. The contributions from steric and electrostatic fields for model 2 were 0.493 and 0.507, respectively. The two highly predictive CoMFA models indicate that the 3α-substituent has two possible binding modes at the DAT. The CoMFA contour maps provide a visual representation of prospective binding modes of the 3α-substituent of the piperidine-based analogues of cocaine and can be used to design novel DAT inhibitors that may be useful for the treatment of cocaine abuse and certain neurological disorders.",
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