Abstract
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 pKi 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 471-493 |
| Number of pages | 23 |
| Journal | Journal of Computer-Aided Molecular Design |
| Volume | 20 |
| Issue number | 7-8 |
| DOIs | |
| State | Published - Aug 1 2006 |
Fingerprint
Keywords
- Comparative modeling
- Docking
- G-protein coupled receptor (GPCR)
- Homology
- Kappa opioid receptor
- Modeler
- Molecular dynamics
- New molecular entities (NMEs)
- Pharmacophore
- Salvinorin A
Cite this
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. / Singh, Nidhi; Chevé, Gwénaël; Ferguson, David M.; McCurdy, Christopher R.
In: Journal of Computer-Aided Molecular Design, Vol. 20, No. 7-8, 01.08.2006, p. 471-493.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A combined ligand-based and target-based drug design approach for G-protein coupled receptors
T2 - Application to salvinorin A, a selective kappa opioid receptor agonist
AU - Singh, Nidhi
AU - Chevé, Gwénaël
AU - Ferguson, David M.
AU - McCurdy, Christopher R.
PY - 2006/8/1
Y1 - 2006/8/1
N2 - 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 pKi 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.
AB - 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 pKi 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.
KW - Comparative modeling
KW - Docking
KW - G-protein coupled receptor (GPCR)
KW - Homology
KW - Kappa opioid receptor
KW - Modeler
KW - Molecular dynamics
KW - New molecular entities (NMEs)
KW - Pharmacophore
KW - Salvinorin A
UR - http://www.scopus.com/inward/record.url?scp=34249277652&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249277652&partnerID=8YFLogxK
U2 - 10.1007/s10822-006-9067-x
DO - 10.1007/s10822-006-9067-x
M3 - Article
C2 - 17009091
AN - SCOPUS:34249277652
VL - 20
SP - 471
EP - 493
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
SN - 0920-654X
IS - 7-8
ER -