Systems Pharmacology Approaches to Personalised Medicin

1. Systems Pharmacology Approaches to Personalised Medicine
Jordi MESTRES
Principal Investigator, IMIM
Associate Professor, UPF
Founder and CEO, Chemotargets

2. Outline of the presentation
• Introduction to systems pharmacology
• Drug safety and the human metabolome
• CLARITY®: predictive analytics platform

3. Outline of the presentation
• Introduction to systems pharmacology
• Drug safety and the human metabolome
• CLARITY®: predictive analytics platform

4. What’s a drug?
Something that I swallow/inject
with therapeutic effect
A chemical entity
with therapeutic effect

5. What’s pharmacology?

6. Drugs are the result of a long optimisation process
Source:NovamassLtd(www.sbw.fi)

7. Drugs exert their action by interacting with proteins

8. The druggable genome
Manning et al., Science 298 (2002) 1912

9. The druggable genome
Hopkins & Groom, Nat Rev Drug Discov 1 (2002) 727

10. Linking targets to diseases: COX-2
Hopkins & Groom, Nat Rev Drug Discov 1 (2002) 727

11. Linking diseases to targets: Pneumonia
www.opentargets.com

12. O
O
O N
O
N
N
HO
NO2
N
+
N
O
O
F
F
N
H
5,0
5,5
6,0
6,5
7,0
7,5
8,0
m
k
d
ORL1
A3
a1
D1
D2
D3
D4
D5
H2
M1
M2
5-HT1A
5-HT2A
5-HT3
5-HT5A
5-HT6
5-HT7
Receptor List
pIC50
1
2
The issue of data completeness
Poulain et al, J Med Chem 44 (2001) 3391

13. O
O
O N
O
N
N
HO
NO2
N
+
N
O
O
F
F
N
H
5,0
5,5
6,0
6,5
7,0
7,5
8,0
m
k
d
ORL1
A3
a1
D1
D2
D3
D4
D5
H2
M1
M2
5-HT1A
5-HT2A
5-HT3
5-HT5A
5-HT6
5-HT7
Receptor List
pIC50
1
2
The issue of data completeness
Poulain et al, J Med Chem 44 (2001) 3391

14. O
O
O N
O
N
N
HO
NO2
N
+
N
O
O
F
F
N
H
5,0
5,5
6,0
6,5
7,0
7,5
8,0
m
k
d
ORL1
A3
a1
D1
D2
D3
D4
D5
H2
M1
M2
5-HT1A
5-HT2A
5-HT3
5-HT5A
5-HT6
5-HT7
Receptor List
pIC50
1
2
Poulain et al, J Med Chem 44 (2001) 3391
The issue of data completeness

15. On drug selectivity…
“Selectivity is our perception of the ability of small
molecules to bind to multiple proteins due to our
limited capacity for screening”
Mestres et al, Nat Biotechnol 26 (2008) 983

16. O
O
O N
O
N
N
HO
NO2
N
+
N
O
O
F
F
N
H
5,0
5,5
6,0
6,5
7,0
7,5
8,0
m
k
d
ORL1
A3
a1
D1
D2
D3
D4
D5
H2
M1
M2
5-HT1A
5-HT2A
5-HT3
5-HT5A
5-HT6
5-HT7
Receptor List
pIC50
1
2
Poulain et al, J Med Chem 44 (2001) 3391
The issue of data completeness
Primary target
Primary pharmacology
Secondary targets
Secondary pharmacology

17. Bromocriptine, a “dopamine agonist”
(N04BC01)

18. 0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7 a1A a1B a1D a2A a2B a2C
pAc vity
Bromocriptine, a “dopamine agonist”

19. 0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7 a1A a1B a1D a2A a2B a2C
pAc vity
Bromocriptine, a “dopamine agonist”

20. Pergolide, another “dopamine agonist”
(N04BC02)

21. 0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7 a1A a1B a1D a2A a2B a2C
pAc vity
Pergolide, another “dopamine agonist”

22. 0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7 a1A a1B a1D a2A a2B a2C
pAc vity
Pergolide, another “dopamine agonist”

23. Bromocriptine (N04BC01) vs Pergolide (N04BC02)
Dopamine Agonists (N04BC)
0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7 a1A a1B a1D a2A a2B a2C
Bromocrip ne
Pergolide

24. On drug classes…
“Drug classes can be misleading and do not reflect
the subtle differences in the pharmacological
profiles of individual drugs”

25. Drug polypharmacology

26. What’s systems pharmacology?

27. What’s systems pharmacology?

28. From preclinical to clinical…

29. …to precision medicine

30. Towards animal free research
Chemical perspectiveGenetic perspective

31. Towards animal free research
Chemical perspectiveGenetic perspective

32. Outline of the presentation
• Introduction to systems pharmacology
• Drug safety and the human metabolome
• CLARITY®: predictive analytics platform

33. Biological systems as chemical containers

34. Biological systems as chemical containers
Endogenous
metabolites
Endogenous
metabolites

35. Biological systems as chemical containers
Endogenous
metabolites
Endogenous
proteins

36. Biological systems as chemical containers
Endogenous
metabolites
Endogenous
proteins

37. Biological systems as chemical containers
Endogenous
metabolites
Endogenous
proteins
Endogenous
metabolites
Endogenous
proteins

38. Biological systems import alien chemical matter
Endogenous
metabolites
Endogenous
proteins
Endogenous
metabolites
Endogenous
proteins

39. Biological systems import alien chemical matter
Endogenous
metabolites
Endogenous
proteins
Exogenous
metabolite
Endogenous
metabolites
Endogenous
proteins

40. Biological systems import alien chemical matter
Endogenous
metabolites
Endogenous
proteins
Exogenous
metabolite
Endogenous
metabolites
Endogenous
proteins

41. Biological systems import alien chemical matter
Endogenous
metabolites
Endogenous
proteins
Exogenous
metabolite
Endogenous
metabolites
Endogenous
proteins

42. Ametabolomics view to precision medicine
1. A drug is an alien
molecule that has
been synthetically
designed to interact
optimally with certain
proteins (targets)
2. Most computational
methods still treat
drugs as isolated
chemical entities

43. Ametabolomics view to precision medicine
1. A drug is an alien
molecule that has
been synthetically
designed to interact
optimally with certain
proteins (targets)
2. Most computational
methods still treat
drugs as isolated
chemical entities
3. Endogenous
metabolites have been
evolutionary designed
to interact optimally
with certain proteins
4. The levels of
endogenous
metabolites vary
across species and
across individuals
5. Genetic and
environmental factors
can ultimately affect
the levels of certain
endogenous
metabolites

44. There is variation in the affinity of drugs for targets

45. There is variation in the affinity of drugs for targets

46. There is variation in the affinity of drugs for targets

47. DrugCentral
4.486 drugs
1.862 drugs
936 drugs
+ interacting against human target labeled
as ‘mechanism of action’
+ Activity values
403
proteins
Guide to Pharmacology
9.144 ligands
113 ligands
175
proteins
454 drug-target-metabolite interactions
301 drugs | 80 proteins | 64 metabolites
Same affinity units
between drug and
metabolite
Why do drugs have a certain
affinity for their primary targets
Drug primary targets and the human metabolome
labeled as principal
endogenous ligand for
at least 1 human target
Bofill et al, Drug Discov Today 24 (2019) 1806

48. Drug Protein
Endogenous
metabolite
Activity
units
Durg
action type
Drug
affinity
Metabolite
maximum
affinity
mianserin 5HT2A
5-hydroxytryptamine
Ki Antagonist 8.17 8.40
mianserin
5HT2C 5-hydroxytryptamine
Ki Antagonist 8.52 8.60
mianserin 5HT2B
5-hydroxytryptamine
Ki Antagonist 8.12 8.40
mifepristone GCR cortisol IC50 Antagonist 9.00 8.00
mirtazapine 5HT2A
5-hydroxytryptamine
Ki Antagonist 7.16 8.40
mirtazapine
5HT2C 5-hydroxytryptamine
Ki Antagonist 7.41 8.60
misoprostol
PE2R3
PGE2 Ki Agonist 6.50 9.48
The human endogenous metabolome as a
pharmacology baseline for drug discovery
Drug primary targets and the human metabolome
Bofill et al, Drug Discov Today 24 (2019) 1806

49. The human endogenous metabolome as a
pharmacology baseline for drug discovery
Drug primary targets and the human metabolome
Bofill et al, Drug Discov Today 24 (2019) 1806

50. The human endogenous metabolome as a
pharmacology baseline for drug discovery
Metabolite Affinity
Baseline (MAB):
metabolite affinity
minus 2 orders of
magnitude
Drug primary targets and the human metabolome
Bofill et al, Drug Discov Today 24 (2019) 1806

51. Drug primary targets and the human metabolome
Bofill et al, Drug Discov Today 24 (2019) 1806

52. This analysis indicates that the affinity of the
endogenous metabolite for its native receptor
could be a good reference baseline for the primary
pharmacology of a drug
Drug primary targets and the human metabolome

53. Serotonin, the endogenous ligand of serotonin receptors
0.00
1.00
2.00
3.00
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5.00
6.00
7.00
8.00
9.00
10.00
5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT1F 5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT4 5-HT5A 5-HT6 5-HT7
Serotonin

54. Pergolide pharmacology in the Metabolome context
0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7
Dopamine/Serotonin
Pergolide
Dopamine Serotonin

55. Impact on drug efficacy
0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7
Dopamine/Serotonin
Pergolide
Dopamine Serotonin

56. Impact on clinical drug safety
0
1
2
3
4
5
6
7
8
9
10
D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT2B 5-HT2C 5-HT6 5-HT7
Dopamine/Serotonin
Pergolide
Dopamine Serotonin

57. Impact on clinical drug safety
“The sustained overstimulation of 5-HT2B either by
high plasma levels of serotonin or by drugs with 5-
HT2B agonist properties can lead to development of
valvular heart disease”

58. 5-HT2B and valvular heart disease
Of the 12 valvulopathic drugs, 5 (42%) have pKi values
equal to or larger than the serotonin affinity, 7 (58%)
within an order of magnitude of the serotonin affinity, and
11 (92%) within two orders of magnitude of the serotonin
affinity.
Of the 12 nonvalvulopathic drugs, 7 (58%) have pKi values
below the MAB. The five nonvalvulopathic drugs found
above the MAB are tretinoin, oxymetazoline, lorcaserin, 5-
MEO-DMT and lysergide. Interestingly, clinical monitoring
on the risk of VHD has been already recommended for
lorcaserin.
List of 24 HTR2B agonist drugs

59. Impact on preclinical translational safety
Serotonin Elisa Kit from Abcam, ab133053
• Different species may well have different levels of
certain metabolites which may affect both the
translational efficacy and safety of drugs

60. Translational safety: false positives
Rat Man
Bofill et al, Drug Discov Today 24 (2019) 1806

61. Translational safety: false negatives
Man Rat
Bofill et al, Drug Discov Today 24 (2019) 1806

62. Translational safety: on- versus off-target selectivity
Bofill et al, Drug Discov Today 24 (2019) 1806

63. The affinity of endogenous ligands for their native
proteins sets the baseline for the
minimum/maximum affinities of drug-target/off-
target interactions
Drug secondary targets and the human metabolome

64. Drug secondary targets and the human metabolome
Most drugs interact with their primary targets with in vitro binding affinities that are more potent than the affinity
values of the corresponding endogenous metabolites
For any given protein being the primary target of a drug, the in vitro binding affinities of endogenous metabolites are
directly proportional to the minimum affinity for a drug
The interactions between drugs and protein off-targets with in vitro binding affinities within two orders of magnitude
from the affinities of endogenous metabolites should be considered of safety concern

65. Our body holds the key to designing safer drugs

66. Outline of the presentation
• Introduction to systems pharmacology
• Drug discovery and the human metabolome
• CLARITY®: predictive analytics platform

67. Rumsfeld Matrix on Knowns and Unknowns
www.opentargets.com

68. CLARITY®: predictive analytics and visualization platform
Chemotargets CLARITY®
The most advanced data analytics and visualization platform
for small molecule pharmaceuticals and cosmeceuticals
ANALYTICS
DATA
MODELS
There is a need to
extract signals
from data and
visualise them
effectively
There is enough
informative data to
generate predictive
models:
Pharmacology
Safety
Metabolism
Indications
…
More data does not
necessarily mean
more information:
urgent need to
integrate multiple
heterogenous data
sources

69. CLARITY®: predictive analytics and visualization platform

70. CLARITY®: predictive pharmacology

71. CLARITY®: predictive safety

72. CLARITY®: predictive safety

73. CLARITY®: predictive metabolism

74. CLARITY®: predictive analytics and visualization platform

75. CLARITY®: predictive analytics and visualization platform

76. Acknowledgments
Dr. Xavier Jalencas
Dr. Albert Antolín
Dra. Viktória Szabo
Andreu Bofill
Ma. José Falaguera
Uxue Lazcano
Dr. Ricard Garcia-Serna
Dr. Nikita Remez
Dr. Joaquim Olivés
Dra. Ma. Carmen Carrascosa
Dr. Oriol López
Pablo Fernández
Dra. Montserrat Cases
Dra. Elisabet Gregori