![Page 1: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/1.jpg)
© 2015 Optibrium Ltd.Optibrium™, StarDrop™ and Card View™ are trademarks of Optibrium Ltd.
Ed Champness, Matt Segall & Peter Hunt
Data Visualisation: New Directions or Just Familiar Routes?
![Page 2: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/2.jpg)
© 2015 Optibrium Ltd.
Overview
• Data Visualisation
• Drug Discovery Data
• Multi-Parameter Optimisation
• Using Data Visualisation to Drive Optimisation
• Conclusions
![Page 3: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/3.jpg)
Using Data Visualisation
![Page 4: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/4.jpg)
© 2015 Optibrium Ltd.
Why use data visualisation?
Our visual system is extremely well built for visual analysis
− The optic nerve is a very big pipe
− Our brains are very good at edge detection, shape recognition and pattern matching
Data visualisation creates powerful, elegant images from complex data. It’s like good prose: a pleasure to experience and a force for good in the right hands, but also seductive and potentially deceptive. … . Too much data visualisation is the statistical equivalent of dazzle camouflage: striking looks grab our attention but either fail to convey useful information or actively misdirect us. (Tim Hartford – Financial Times)
(Noah Iliinsky, Amazon Web Services, ComplexDiagrams.com)
BUT…
![Page 5: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/5.jpg)
© 2015 Optibrium Ltd.
Use of data visualisationWhen the statistics deceive us…
en.wikipedia.org/wiki/Anscombe%27s_quartet
Anscombe’s quartet
Property Value
Mean(x) 9
Variance(x) 11
Mean(y) 7.5 (2dp)
Variance(y) 4.122 or 4.127 (3dp)
Pearson r 0.816 (3dp)
Linear regression
y = 3 + 0.5x (2dp)
![Page 6: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/6.jpg)
© 2015 Optibrium Ltd.
Misuse of data visualisation
Ravi Parikh - Heap Analytics:gizmodo.com/how-to-lie-with-data-visualization-1563576606
![Page 7: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/7.jpg)
© 2015 Optibrium Ltd.
Misuse of data visualisation
Inflation of correlation in the pursuit of drug-likeness.Kenny, Montanari - J Comput Aided Mol Des. 2013 Jan;27(1):1-13
From binning this data…
![Page 8: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/8.jpg)
© 2015 Optibrium Ltd.
Colour can have the wrong impact…
www.grand-illusions.com/opticalillusions/square/
![Page 9: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/9.jpg)
© 2015 Optibrium Ltd.
Misuse of data visualisationUsing a good visualisation for the wrong purposes…
Sayf Shariflunametrics.com/blog/2013/02/04/power-danger-data-visualization
![Page 10: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/10.jpg)
© 2015 Optibrium Ltd.
Misuse of data visualisationUsing a good visualisation for the wrong purposes…
Sayf Shariflunametrics.com/blog/2013/02/04/power-danger-data-visualization
![Page 11: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/11.jpg)
© 2015 Optibrium Ltd.
Back to drug discovery…
Let’s looks at some drug discovery data:
− Library of 264 5HT1a compounds
− Measured potencies and other ADME/physicochemical properties
− Six different chemotypes:
2(arylcycloalkylamine) 1-indanols (27)
Arylpiperazines (120) Arylpiperidines(17)
Aminotetralines(51)
N-aryloxyethylindolealkylamines(29)
Aporphines (20)
Let’s think about how we might prioritise these…
![Page 12: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/12.jpg)
© 2015 Optibrium Ltd.
Let’s start with potency
![Page 13: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/13.jpg)
© 2015 Optibrium Ltd.
Let’s start with potency – with error bars
![Page 14: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/14.jpg)
© 2015 Optibrium Ltd.
Box plot gives a clearer picture
![Page 15: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/15.jpg)
© 2015 Optibrium Ltd.
Other properties: logP
![Page 16: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/16.jpg)
© 2015 Optibrium Ltd.
Other properties: Solubility (logS)
![Page 17: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/17.jpg)
© 2015 Optibrium Ltd.
Other properties: BBB penetration
![Page 18: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/18.jpg)
© 2015 Optibrium Ltd.
Other properties: hERG pIC50
![Page 19: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/19.jpg)
© 2015 Optibrium Ltd.
Seeing them all together?
![Page 20: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/20.jpg)
© 2015 Optibrium Ltd.
Seeing them all together
Card View™
![Page 21: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/21.jpg)
Drug Discovery Data
![Page 22: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/22.jpg)
© 2015 Optibrium Ltd.
Data in drug discovery
• What’s certain?
− We know some simple properties of our compounds
• What’s not so certain?
− In vitro/In vivo measurements
o experimental variability
− In silico predictions
o statistical error
− Inference/translation
22
![Page 23: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/23.jpg)
© 2015 Optibrium Ltd.
The Challenges:Uncertain data
• So what does that mean…
• A good RMSE for logS (solubility) is 0.6
• Assuming normal distribution this means that when we have a logS value of 2 (that’s 100µM) then
− 68% of the time this represents an actual value between 1.4 and 2.6 (25µM to 400µM)
− 95% of the time this represents an actual value between 0.8 and 3.2 (6µM to 1.6mM)
− 99% of the time this represents an actual value between 0.2 and 3.8 (1.6µM to 6.3mM)
23
![Page 24: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/24.jpg)
© 2015 Optibrium Ltd.
X
Property Y
100 10 1 0.1
Desired value > Threshold
A B C
UNDESIRABLE DESIRABLE
Importance of Uncertainty
X X X X
![Page 25: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/25.jpg)
© 2015 Optibrium Ltd.
Importance of Uncertainty
100 10 1 0.1
Desired value > Threshold
D E
UNDESIRABLE DESIRABLE
Property Z
![Page 26: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/26.jpg)
© 2015 Optibrium Ltd.
The Challenges:…and one more thing
• We probably have quite a few properties we need to optimise!
− Each will have their own uncertainty
− Each will have its own criteria we’d like to achieve
− Each will have its own level of importance relative to the other properties
26
![Page 27: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/27.jpg)
Multi-Parameter Optimisation
![Page 28: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/28.jpg)
© 2015 Optibrium Ltd.
Back to our 5HT1a library
• Example criteria we might like to achieve for an ideal compound
Property Desired value Importance
Potency (pKi) > 7 High
logS (log µM) > 1 High
Human IntestinalAbsorption (category)
+ High
BBB log([brain]:[blood]) -0.2 -> 1 High
logP 0 -> 3.5 Medium
P-gp (category) No Medium
hERG pIC50 ≤ 5 Medium
2C9 pKi ≤ 6 Low
2D6 affinity (category) Low/Medium Low
Plasma protein binding (category)
Low Low
![Page 29: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/29.jpg)
© 2015 Optibrium Ltd. 29
Putting it all together (MPO):Probabilistic Scoring* – Scoring Profile
* Segall et al. (2009) Chem. & Biodiv. 6 p. 2144
![Page 30: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/30.jpg)
© 2015 Optibrium Ltd.
Multi-parameter OptimisationProbabilistic Scoring*
• Property data
− Experimental or predicted
• Criteria for success
− Relative importance
• Uncertainties in data
− Experimental or statistical
• Score (Likelihood of Success)• Confidence in score
Sco
re
Best Worst
Error bars show confidence in overall score
Data do not separate these as error bars overlap
Bottom 50% may be rejected with confidence
*M.D. Segall (2012) Curr. Pharm. Des. 18(9) pp. 1292-1310
Compounds ordered by score
![Page 31: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/31.jpg)
© 2015 Optibrium Ltd.
Snake plot for complete library
![Page 32: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/32.jpg)
© 2015 Optibrium Ltd.
Stacks for each chemistry type show distribution of scores
![Page 33: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/33.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 34: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/34.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 35: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/35.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 36: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/36.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 37: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/37.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 38: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/38.jpg)
© 2015 Optibrium Ltd.
Each chemistry in turn
![Page 39: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/39.jpg)
© 2015 Optibrium Ltd.
An appropriate selection?
(N.B. There are 2.77 x 1054 possible ways to select 50 compounds)
![Page 40: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/40.jpg)
Using Data Visualisation to Drive Optimisation
![Page 41: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/41.jpg)
© 2015 Optibrium Ltd.
Focusing on the arylpiperazines
• One subset of these are Buspirone analogues
• Measured potency with pkisbetween 5.8 and 8.7
• Measure stability (CYP3A4 half-life) between 3 and 80 minutes
• 20 analogues
![Page 42: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/42.jpg)
© 2015 Optibrium Ltd.
SAR tables
StabilityPotency
![Page 43: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/43.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhood
![Page 44: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/44.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhoodGood potency, poor stability
![Page 45: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/45.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhoodGood stability, poor potency
![Page 46: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/46.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhoodGood potency, poor stability
![Page 47: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/47.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhoodBest of both worlds
![Page 48: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/48.jpg)
© 2015 Optibrium Ltd.
Activity neighbourhoodBest of both worlds
![Page 49: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/49.jpg)
© 2015 Optibrium Ltd.
Conclusions
• It is very often the network of inter-relationships between compounds that matter
− These often influence the creation of the next compound
• The way we perceive our compounds depends upon those around it
− Timing: have we explored the surrounding chemical space thoroughly enough to adequately evaluate a series?
− Property data: do we have data of sufficient quality to confidently distinguish the good compounds?
• Visualisations that collapse or remove that network relationship and context always have the potential to bias our perception of the data.
49
![Page 50: Data Visualisation: New directions or just familiar routes? · © 2015 Optibrium Ltd. Back to our 5HT1a library •Example criteria we might like to achieve for an ideal compound](https://reader034.vdocuments.us/reader034/viewer/2022042310/5ed7c8ca7626b373466bc600/html5/thumbnails/50.jpg)
© 2015 Optibrium Ltd.
Acknowledgements
• Matt Segall
• Peter Hunt
• Chris Leeding
• James Chisholm
• Hector Garcia Martinez
• Alex Elliott
• Sam Dowling
• Nick Foster
• Exhibition booth #417/516
• CINF 162: Modeling ABC transporters as potential DILI targets – Matt Segall− Weds 19 August 15:50 – 16:10 : Room 103
50