1. Reporter: Yu Lun Kuo (D95922037) E-mail: sscc6991@gmail.com
Protein-Based Virtual Screening of Chemical Database. II. Are Homology Models of G-Protein Coupled Receptors Suitable Targets?
PROTEINS: Structure, Function, and Genetics 50:5–25 (2003)
Reporter: Yu Lun Kuo (D )
Date: June 26, 2007

2. Abstract
Investigate whether homology models of G-Protein Coupled Receptors (GPCRs)
Based on bovine rhodopsin
Homology models of an antagonist-bound form of three human GPCRs
Dopamine D3 receptor
Muscarinic M1 receptor
Vasopressin V1a receptor
2019/2/22

3. Abstract Homology models of an agonist-bound form of three human GPCRs
D3 receptor
β2 receptor
δ-opioid receptor
Building agonist-bound models
S1 model
S2 model
M model
2019/2/22

4. Abstract
The homology models were used to screen three-dimensional databases using three different docking program
Dock
FlexX
Gold
Combination with seven scoring functions
ChemScore, Dock, FlexX, Fresno, Gold, Pmf, Score
2019/2/22

5. Introduction
The available databases get larger and larger, the costs of such screenings rise whereas the hit rate decrease
Not to screen the whole database experimentally but only a small subset
2019/2/22

6. This is notably true for G-Protein coupled receptor (GPCRs)
Represent one of the most important families of pharmaceutical targets
Thus, there is high interest in developing new lead compounds for most human GPCRs
2019/2/22

7. We investigated whether rhodopsin-based GPCR homology models are reliable enough for carrying out virtual screening of chemical libraries focused on either antagonists or agonist ligands of test GPCRs
Consensus scoring was then applied to generate small subsets (hit lists) comprising only the top scores
common to two or three scoring lists
2019/2/22

8. Alignment of Amino Acid Sequences
The amino acid sequences of the five receptors were retrieved from the Swiss-Prot database
Human dopamine D3 receptor
Human muscarinic acetylcholine M1 receptor
Human vasopressin V1a receptor
Human β2-adrenergic receptor
Human δ-opioid receptor
Aligned to the sequence of bovine rhodopsin
2019/2/22

9. Consensus Scoring: Definition of a Hit List
Having rescored the docked poses with these seven scoring functions
D3, V1a, and β2 receptor, defined the top 15% of the individual ranking list as top scorers
δ-opioid receptor, the top 20% scores were selected
M1 receptor, the top 25% scores were retrieved
A pairwise comparison of the lists of top scores yielded the consensus lists (hit lists)
2019/2/22

10. Descriptors of the Hit Lists
Two properties of every generated hit list were computed
Hit rate
Hit yield
Hit Rate = (t / l) x100
Yield = ( t / T) x100
t = # of true hits in the hit list
l = # of compounds in the hit list
T = # of true hits in the full database
2019/2/22

11. Structure of receptor antagonist
D3 atagonist
V1a antagonist
M1 antagonist
2019/2/22

12. Structure of receptor agonist
D3 agonist
2019/2/22

13. Virtual Screening of Receptor Antagonists
2019/2/22

14. Virtual Screening of Receptor Agonists
2019/2/22

15. 2019/2/22

16. Crossdocking Experiments
2019/2/22

17. Conclusion For the D3 and V1a receptor
Obtained hit rates are 20- to 40- fold higher than what can be obtained by random screening
This very important feature should enable us to retrieve new lead structures that could be totally unrelated to any know GPCR ligand
2019/2/22

18. Thanks for your attention
2019/2/22