caa a22 4500 467938652 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060801xx s 000 0 eng 10.1007/s10822-006-9067-x doi (NATIONALLICENCE)springer-10.1007/s10822-006-9067-x A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist [Elektronische Daten] [Nidhi Singh, Gwénaël Chevé, David Ferguson, Christopher McCurdy] Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based "agonist-bound” hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental pK i values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs. Springer Science+Business Media, LLC, 2006 Salvinorin A nationallicence Pharmacophore nationallicence G-protein coupled receptor (GPCR) nationallicence Comparative modeling nationallicence Modeler nationallicence Molecular dynamics nationallicence Docking nationallicence Kappa opioid receptor nationallicence Homology nationallicence New molecular entities (NMEs) nationallicence Singh Nidhi Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut Chevé Gwénaël Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut Ferguson David Department of Medicinal Chemistry, The University of Minnesota, 55455, Minneapolis, MN, USA aut McCurdy Christopher Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 471-493 0920-654X 20:7-8<471 2006 20 10822 https://doi.org/10.1007/s10822-006-9067-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9067-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Singh Nidhi Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut NATIONALLICENCE 700 1- Chevé Gwénaël Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut NATIONALLICENCE 700 1- Ferguson David Department of Medicinal Chemistry, The University of Minnesota, 55455, Minneapolis, MN, USA aut NATIONALLICENCE 700 1- McCurdy Christopher Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, 38677, University, MS, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 471-493 0920-654X 20:7-8<471 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer