P2Y1 antagonists: An analysis of the structural elements of ligand recognition based on molecular docking and 3D-QSAR

MEDI 428

Stefano Costanzi, stefanoc@intra.niddk.nih.gov1, Michihiro Ohno, michihiroo@intra.niddk.nih.gov2, Eun Joo Roh2, Bhalchandra V. Joshi, BalachandraJ@intra.niddk.nih.gov2, Anny-Odile Colson1, Dayle Houston3, Savitri Maddileti3, T. Kendall Harden3, and Kenneth Jacobson, kajacobs@helix.nih.gov2. (1) Computational Chemistry Core Laboratory, NIDDK, National Institutes of Health, 12A Center Drive Rm 4051 MSC 5646, Bethesda, MD 20892-5646, (2) Molecular Recognition Section, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, (3) School of Medicine, Univ. of North Carolina, Chapel Hill
A 3D-QSAR study has been carried out on a series of pseudonucleoside antagonists of the P2Y1 receptor, synthesized in our laboratories in the course of the last decade. All the ligands were docked in the putative nucleotide binding site of our rhodopsin based human P2Y1 homology model. The resulting alignment was subjected to a Comparative Molecular Field Analysis (CoMFA), aimed at quantitatively correlating the activity of the antagonists with their molecular structures. Docking of the CoMFA model into the human P2Y1 homology model allowed linking of the structural features of the receptor to the QSAR data and the obtained steric and electrostatic contour maps. Furthermore, in an effort to validate the predictive performances of our models and to further explore the SAR of the P2Y1 antagonists, six novel compounds were synthesized and tested for their ability to inhibit 2-MeSADP stimulated PLC activity and to displace a radioligand in binding assays.
 

General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006