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 (D95922037) E-mail: sscc6991@gmail.com Date: June 26, 2007

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

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

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

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

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

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

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

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

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

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

Structure of receptor agonist D3 agonist 2019/2/22

Virtual Screening of Receptor Antagonists 2019/2/22

Virtual Screening of Receptor Agonists 2019/2/22

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Crossdocking Experiments 2019/2/22

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

Thanks for your attention 2019/2/22