High-affinity interactions of ligands at recombinant Guinea pig 5HT7 receptors |
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Authors: | RE Wilcox JE Ragan RS Pearlman MY-K Brusniak RM Eglen DW Bonhaus TE Tenner Jr JD Miller |
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Institution: | (1) College of Pharmacy, University of Texas at Austin, TX 78712 Austin, USA;(2) DiscoveRx Corporation, Fremont, CA 94538, USA;(3) Roche Biosciences, Palo Alto, CA 94304, USA;(4) Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA |
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Abstract: | The serotonin 5HT7 receptor has been implicated in numerous physiological and pathological processes from circadian rhythms 1] to depression and schizophrenia. Clonal cell lines heterologously expressing recombinant receptors offer good models for understanding drug-receptor interactions and development of quantitative structure-activity relationships (QSAR). Comparative Molecular Field Analysis (CoMFA) is an important modern QSAR procedure that relates the steric and electrostatic fields of a set of aligned compounds to affinity. Here, we utilized CoMFA to predict affinity for a number of high-affinity ligands at the recombinant guinea pig 5HT7 receptor. Using R-lisuride as the template, a final CoMFA model was derived using procedures similar to those of our recent papers 2, 3, 4] The final cross-validated model accounted for >85% of the variance in the compound affinity data, while the final non-cross validated model accounted for >99% of the variance. Model evaluation was done using cross-validation methods with groups of 5 ligands. Twenty cross-validation runs yielded an average predictive r2(q2) of 0.779 ± 0.015 (range: 0.669–0.867). Furthermore, 3D-chemical database search queries derived from the model yielded hit lists of promising agents with high structural similarity to the template. Together, these results suggest a possible basis for high-affinity drug action at 5HT7 receptors. |
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Keywords: | agonist affinity computer-aided design comparative molecular field analysis serotonin receptors recombinant receptors |
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