RT Journal Article
SR Electronic
T1 Proteochemometric Mapping of the Interaction of Organic Compounds with Melanocortin Receptor Subtypes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 50
OP 59
DO 10.1124/mol.104.002857
VO 67
IS 1
A1 Maris Lapinsh
A1 Santa Veiksina
A1 Staffan Uhlén
A1 Ramona Petrovska
A1 Ilze Mutule
A1 Felikss Mutulis
A1 Sviatlana Yahorava
A1 Peteris Prusis
A1 Jarl E. S. Wikberg
YR 2005
UL http://molpharm.aspetjournals.org/content/67/1/50.abstract
AB Proteochemometrics was applied in the analysis of the binding of organic compounds to wild-type and chimeric melanocortin receptors. Thirteen chimeric melanocortin receptors were designed based on statistical molecular design; each chimera contained parts from three of the MC1,3-5 receptors. The binding affinities of 18 compounds were determined for these chimeric melanocortin receptors and the four wild-type melanocortin receptors. The data for 14 of these compounds were correlated to the physicochemical and structural descriptors of compounds, binary descriptors of receptor sequences, and cross-terms derived from ligand and receptor descriptors to obtain a proteochemometric model (correlation was performed using partial least-squares projections to latent structures; PLS). A well fitted mathematical model (R2 = 0.92) with high predictive ability (Q2 = 0.79) was obtained. In a further validation of the model, the predictive ability for ligands (Q2lig = 0.68) and receptors (Q2rec = 0.76) was estimated. The model was moreover validated by external prediction by using the data for the four additional compounds that had not at all been included in the proteochemometric model; the analysis yielded a Q2ext = 0.73. An interpretation of the results using PLS coefficients revealed the influence of particular properties of organic compounds on their affinity to melanocortin receptors. Three-dimensional models of melanocortin receptors were also created, and physicochemical properties of the amino acids inside the receptors' transmembrane cavity were correlated to the PLS modeling results. The importance of particular amino acids for selective binding of organic compounds was estimated and used to outline the ligand recognition site in the melanocortin receptors.