Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment.
Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level.
Iskander
Magdy N
MN
The Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia. magdy.iskander@vcp.monash.edu.au
Leung
Lok M
LM
Buley
Trevor
T
Ayad
Fadi
F
Di Iulio
Juliana
J
Tan
Yean Y
YY
Coupar
Ian M
IM
D001665:Binding Sites; D050483:Dopamine Plasma Membrane Transport Proteins; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4