The document presents a case study on the overlapping chemical space of renin-angiotensin system inhibitors, describing the analysis of various molecules and scaffolds using the Aurscope and Aurprofiler tools. It details the testing of 2164 molecules, focusing on their activity against AGTR2 and related enzymes, and outlines the methodology for identifying active chemical structures. Future steps include deeper analysis of candidate molecules and development of a new methodology for exploring shared chemical spaces.

1. Make the right decisions with data you can trustCase Study: Overlapping chemical space of renin-angiotensin system inhibitors© 2011 Ariadne. All Rights Reserved.© 2011 Aureus. All Rights Reserved.

2. Renin-Angiotensin system In pathway studioTargeted enzymesTargetedReceptorsEnzymes founduponfurtheranalysis

3. Renin-angiotensin system : gene, protein

4. Molecules Tested in vitro on Renin-angiotensin system (AurSCOPE GPS source)

5. MoleculesTestedin vitro as inhibitors on Renin-angiotensin system (GPS source)2164521313131317384017321(309 CPA)177075410583101Targeted enzymesTargetedReceptorsEnzymes foundafterfurtheranalysis

6. Takingadvantage of AurSCOPE Global PharmacologySpaceAurQUESTAurPROFILERSubstructure

7. Chemical Similarity

8. 2D PharmacophoricSimilarity

9. Substructure

10. Chemical SimilarityOverlapping chemical space of renin-angiotensin system inhibitors : Approach using AurPROFILER7123AureusBiologicalSpaceAureusChemicalSpace45

11. MoleculesTested on AGTR2 and Renin-Angiotensin system enzymes using AurPROFILER and AurSCOPE GPS18 MoleculesRestriction Used in AurPROFILER Peptides are excluded

12. Molecular weight< 900

13. Parameters used in AurPROFILERX

14. Molecules active on AGTR2 and Renin-Angiotensin system enzymes (AurSCOPE GPS)14 Molecules

15. Bemis and Murcko Scaffolds tested on AGTR2 and Renin-Angiotensin enzymes using AurPROFILER and AurSCOPE GPS28 Bemis and Murcko Scaffolds represent 537 Molecules X

16. Bemis and Murcko Scaffolds active on AGTR2 and Renin-Angiotensin enzymes using AurPROFILER and AurSCOPE GPS18 Active Scaffolds on the two systems are displayed : 341 Molecules coming from 103 Articles 31 Patents

17. Active Bemis and Murcko Scaffolds Rank by molecule count 123426789101112131415161718

18. Moleculesfrom Active Bemis and MurckoScaffolds : Targets-Ligands NetworkBemis&MurckoFrameworkspAureusBiologicalActivity:510

19. MoleculesTested on AGTR2 and Renin-Angiotensin system enzymes using AurPROFILER and ChEMBL_07ACERestriction Used in AurPROFILER Peptides are excluded

20. Molecular weight< 900

21. Parameters used in AurPROFILERXAT2/ACE2 : 0AT2/neprilysin : 0 AT2/CTSA : 0AT2 /CPA3 : 0AT2/Neurolysin : 0AT2/Thimet : 0AT2/Chymase : 0AT2/Cathepsin G : 0MAS1 receptorwas not found in ChEMBL

22. Losatran inhibits both AGTR2 and ACE

23. Some 4 rings assemblies inhibit both ACE and AGTR2AT2 or ATACE or ACE2

24. ExpendituresApproximately 8 man-hours of PhD scientist time.Subsequent analyses take less time as it will leverage configuration changes made for the 1st analysisPathway Studio 8 + ChemEffect DatabaseAureus Global Pharmacy Space + AurProfiler

25. Next Steps1) Analyse in depth molecules related to Scaffolds tested on Angiotensinrecepotors (AT2) and enzymes of the Renin-angiotensin system 2) Define a new methodology (Bemis and Murcko Scaffold was used in this analysis) to find Shared Chemical space