Quantitative conformationally sampled pharmacophore for μ opioid ligands

COMP 260

Ji Hyun Shim, jshim001@umaryland.edu1, Andrew Coop2, and Alexander D. MacKerell Jr.1. (1) Department of Pharmaceutical Sciences, University of Maryland, 20 Penn St., Baltimore, MD 21201, (2) Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 Penn Street, Baltimore, MD 21201
μ-opioid ligands, the most effective analgesics, have been the constant object of lead modification and optimization for the purpose of overcoming their adverse effect. However their structural diversity and significant differences in pharmacological activity associated with subtle modifications hampered development of a consensus pharmacophore to differentiate agonists and antagonists. The recent development of the Charmm General Force Field (CGenFF) and Conformationally Sampled Pharmacophore (CSP) method provides a new approach for this challenging task. CGenFF is an organic force field for drug-like molecules and parameterized based on large set of model compounds. CGenFF was extended to cover the opioids and validated based on the reproduction of quantum mechanical and crystal data. Based on 33 nonpeptidic and peptidic compounds, which have been selected as representative ligands, we carried out CSP modeling to discriminate agonists from antagonists. Efforts include implementation of an automated pharmacophore searching procedure and regression models for affinity and efficacy were explored. Predictability of the model and its physical meanings will be discussed.

Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster

Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009