Understanding DP receptor antagonism using a CoMSIA approach

  • Bioorg Med Chem Lett. 2011 Jan 1;21(1):66-75. doi: 10.1016/j.bmcl.2010.11.071.
Lan Mu  1 ,  Joacy Aguiar ,  Ali Ardati ,  Bin Cao ,  Charles J Gardner ,  Tim Gillespy ,  Keith Harris ,  Sungtaek Lim ,  Robert Marcus ,  Isabelle Morize ,  Ashfaq Parkar ,  David Stefany ,  Yi Li ,  Roy J Vaz ,  Dragan A Cirovic
Affiliations
  • 1. Sanofi Aventis US, 1041 Route 202-206 N, Bridgewater, NJ 08807-0800, United States.
PMID: 21147533 DOI: 10.1016/j.bmcl.2010.11.071
Abstract

A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set.

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