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Case Study: Overlapping chemical space of renin-

angiotensin system inhibitors

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Renin-Angiotensin system In pathway studio

Targeted enzymes

Targeted Receptors

Enzymes found upon further analysis

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Renin-angiotensin system : gene, protein

Gene name Protein Name UniprotKB ID(Human)

ACE2 Angiotensin-converting enzyme 2 Q9BYF1

ACE Angiotensin-converting enzyme P12821

CTSA (PPGB)Cathepsin A, Carboxypeptidase-L Carboxypeptidase C, serine carboxypeptidase A

P10619

CPA3 Mast cell carboxypeptidase A carboxypeptidase A3 P15088

MME (EPN) Neprilysin P08473

NLN Neurolysin, mitochondrial Q9BYT8

THOP1 Thimet oligopeptidase P52888

CMA1 Chymase P23946

CTSG Cathepsin G P08311

AGTR2AT2, Angiotensine II Receptor 2,Type-2 angiotensin II receptor

P50052

MAS1Angiotensin receptor (1-7), AT3, Type-3 angiotensin II receptor

P04201

MAS1L P35410

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

Gene name Protein Name Molecules tested Inhibitorstested

ACE2 Angiotensin-converting enzyme 2 183 173

ACE Angiotensin-converting enzyme 2204 2164

CTSA (PPGB)Cathepsin A, Carboxypeptidase-L Carboxypeptidase C, Lysosomal carboxypeptidase

84 84

CPA3Mast cell carboxypeptidase A carboxypeptidase A3

0(CPA 323)

0(CPA 309)

MME (EPN) Neprilysin 1325 1313

NLN Neurolysin, mitochondrial 2 2

THOP1 Thimet oligopeptidase 1 1

CMA1 Chymase 1058 1058

CTSG Cathepsin G 785 754

AGTR2AT2, Angiotensine II Receptor 2,Type-2 angiotensin II receptor

1789 (AT 3230)

1770(AT 3101)

MAS1Angiotensin receptor (1-7), AT3, Type-3 angiotensin II receptor

23 16

MAS1L 46 36

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MoleculesTested in vitro as inhibitors on Renin-angiotensin system (GPS source)

Targeted enzymes

Targeted Receptors

Enzymes found after further analysis

2164

1313

2

1

173173840

7541058

52

1770

(309 CPA)

1313

3101

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Taking advantage of AurSCOPE Global Pharmacology Space

AurPROFILER

• Substructure • Chemical Similarity• 2D Pharmacophoric Similarity

• Substructure • Chemical Similarity

AurQUEST

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Overlapping chemical space of renin-angiotensin system inhibitors : Approach using AurPROFILER

Aureus

Chemic

al

Space

Aureus

Biolo

gical

Space

1 2 3

4

5

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Molecules Tested on AGTR2 and Renin-Angiotensin system enzymes using AurPROFILER and AurSCOPE GPS

Restriction Used in AurPROFILER - Peptides are excluded- Molecular weight< 900- Parameters used in AurPROFILER

X

18 Molecules

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

14 Molecules

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Bemis and Murcko Scaffolds tested on AGTR2 and Renin-Angiotensin enzymes using

AurPROFILER and AurSCOPE GPS

28 Bemis and Murcko Scaffolds represent 537 Molecules

X

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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

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Active Bemis and Murcko Scaffolds Rank by molecule count

1 2 3 4

2

9

17

6 7 8

10 11 12

14 15 16

18

13

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Molecules from Active Bemis and Murcko Scaffolds : Targets-Ligands Network

Biological Activity:

Bemis&Murcko Frameworks

pAureus

5 10

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Molecules Tested on AGTR2 and Renin-Angiotensin system enzymes using AurPROFILER and ChEMBL_07

Restriction Used in AurPROFILER - Peptides are excluded- Molecular weight< 900- Parameters used in AurPROFILER

X

AT2/ACE2 : 0AT2/neprilysin : 0 AT2/CTSA : 0AT2 /CPA3 : 0AT2/Neurolysin : 0AT2/Thimet : 0AT2/Chymase : 0AT2/Cathepsin G : 0

ACE

MAS1 receptor was not found in ChEMBL

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Losatran inhibits both AGTR2 and ACE

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Some 4 rings assemblies inhibit both ACE and AGTR2

AT2 or AT ACE or ACE2

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Expenditures

• Approximately 8 man-hours of PhD scientist time.– Subsequent

analyses take less time as it will leverage configuration changes made for the 1st analysis

• Pathway Studio 8 + ChemEffect Database

• Aureus Global Pharmacy Space + AurProfiler

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Next Steps1) Analyse in depth molecules related to Scaffolds tested on

Angiotensin recepotors (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