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Toy example of using bioinformatics and cheminformatics to look for compounds that inhibit more than one target in metabolic pathway
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© 2011 Aureus. All Rights Reserved. © 2011 Ariadne. All Rights Reserved.Confidential. Do not distribute
Make the right decisions with data you can trust
Case Study: Overlapping chemical space of renin-
angiotensin system inhibitors
© 2011 Ariadne. All Rights Reserved.
© 2011 Aureus. All Rights Reserved.
© 2011 Aureus. All Rights Reserved. © 2011 Ariadne. All Rights Reserved.
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
