CoMFA Study of Piperidine Analogues of Cocaine at the Dopamine Transporter: Exploring

the Binding Mode of the 3-Substituent of the Piperidine Ring Using Pharmacophore-Based

Flexible Alignment

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

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago

J. Med. Chem. 2004, 47, 6137-6143

outline• Goal: to develop a model of the dopamine transporter (DAT)

using QSAR analysis of cocaine analogues– No crystal structure of the DAT is available, but many piperidine

analogues of cocaine have been synthesized and evaluated for binding affinity

– A highly predictive model for the DAT would facilitate development of therapeutics for cocaine abuse

• Methods– Training set of 36 compounds, test set of 6 compounds– Genetic Algorithm Similarity Program (GASP) used to generate

pharmacophore by comparing known ligands for DAT– Comparative molecular field analysis (CoMFA) calculates steric and

electrostatic field energies– Refined with Flexible Superposition (FlexS)

Cocaine and analogues

N

O

O

O

OMe

lipophilic

H-bond or dipole-dipoleionic orH-bond

cocaine

N

Ar

R

tropane-based

N

indamine-based

N

Ar

R

piperidine-based

Flow chart

training set

Top two pharmacophores

N

Me

N

NO

O

O

Cl

ligand =

DS = H-bond donorAS = H-bond acceptor siteAA = H-bond acceptor atom

Quantitative predictions are accurate

Conclusions

• Two pharmacophore models suggest multiple binding modes for ligands

• Good fit when QSAR applied to test set of 6 compounds

• Predictive power for new potential therapeutics