Conformationally sampled pharmacophore for δ opioid ligands

COMP 174

Denzil Bernard, dbern002@umaryland.edu1, Andrew Coop1, and Alexander D. MacKerell Jr., alex@outerbanks.umaryland.edu2. (1) Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, (2) Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21201
The use of low energy conformers of ligands in pharmacophore development neglects the dynamic nature of receptor-ligand interactions and does not insure inclusion of the interacting conformers in pharmacophore determination. A conformationally sampled pharmacophore (CSP), which increases the probability of including the receptor bound form of the ligand, may be obtained by including all possible conformations of a ligand in pharmacophore development. This method, previously used in the development of a non-peptidic δ opioid activity pharmacophore, was extended to peptidic δ opioid ligands. Conformational sampling was achieved by replica exchange MD simulations and the pharmacophore developed from measured geometric parameters. Quantitative prediction of efficacy by the CSP was assessed by the use of overlap integrals, with BW373U86 as the reference molecule. A maximum distance criterion from the aromatic to the hydrophobic group in the ligands and equal weighting to all points in conformer space gave improved predictions.