Pre-competitive Collaboration: Sharing Data to Increase

Predictability

Jean-Claude Bradley

October 17, 2011

3rd Annual Drug Discovery Partnership: Filling the Pipeline

Associate Professor of ChemistryDrexel University

Opportunities for Competitive Collaboration

Industry is Sharing More

Solubility and Melting Points

are critical properties in the drug discovery

process

Data quality is essential for both

measurements and predictions based on

measurements

Openness is proving to be a powerful tool for

assessing the reliability of data

Solubility prediction for Taxol using Abraham descriptors

Pred Exp

Predicted temperature dependent solubility of Taxol in water based on

melting point (M)

The Trusted Source ModelBefore online databases (early 90s) searching for properties like melting

points using ONE “trusted source” was practical and acceptable as part of the

chemistry culture.• CRC Handbook• Merck Index• Chemical Vendor Catalogs (e.g. Sigma-Aldrich)

• Peer-Reviewed Journals

Single values don’t tend to be contradicted

Question Assumptions

Using technology, we can begin to replace the “trusted source”

model with one based on transparency and provenance

The Chemical Information Validation Sheet

567 curated and referenced measurements from Fall 2010 Chemical Information Retrieval course

Discovering outliers for melting points (stdev/average)

Investigating the m.p. inconsistencies of EGCG

Investigating the m.p. inconsistencies of cyclohexanone

Most popular data sources

Alfa Aesar donates melting points to the public

Open Melting Point Explorer

(Andrew Lang)

OutliersMDPI

datasetPhysProp (EPA

donated all data to public also)

Outliers for ethanol: Alfa Aesar and Oxford MSDS

Inconsistencies and SMILES problems within MDPI dataset

MDPI Dataset labeled with High Trust Level

Open Melting Point DatasetsCurrently 27,000 mps for 20,000 compounds

American Petroleum Institute 5 CPHYSPROP -30 CPHYSPROP 125 Cpeer reviewed journal (2008) 97.5 Cgovernment database -30 Cgovernment database 4.58 C

What is the melting point of 4-benzyltoluene?

The quest to resolve the melting point of 4-benzyltoluene: liquid at room temp and can be frozen <-30C (Evan Curtin)

Open Lab Notebook page measuring the melting point of 4-benzyltoluene

Motivation: Faster Science, Better Science

Ruling out all melting points above -15C?

Oops – 4-benzyltoluene freezes after 16 days at -15C!

Measuring the melting point by slowly heating from -15 C gives 5 C

There are NO FACTS, only measurements embedded

within assumptions

Open Notebook Science maintains the integrity of data

provenance by making assumptions explicit

TRUST

PROOF

Common errors in datasets

multiple melting points for the same compound in the same database

stereochemistry issues sign inversion conversion errors (Kelvin/Celcius

Fahrenheit/Celcius) bad SMILES (non-rendering) salts associated with SMILES for free base using boiling point for melting point

Open Random Forest modeling of Open Melting Point data using CDK descriptors

(Andrew Lang)

R2 = 0.78, TPSA and nHdon most important

Melting point prediction service

Melting point predictions and measurements on iPhone/iPad (Andrew Lang and Alex Clark)

Publication of double+ validated melting point dataset to Nature

Precedings and LuLu

Crowdsourcing Solubility Data

ONS Challenge Judges

ONS Challenge Award Winners

Web services for summary data

(Andrew Lang)

Reaction Attempts Book

Reaction Attempts Book: Reactants listed Alphabetically

Interactive NMR spectra using JSpecView or ChemDoodle and the Open JCAMP-DX

format

Predicting Best Solvent for Imine Formation using solubility and melting

point data (Evan Curtin)

Predicting Yield of Imine Formation in Ethanol

(Evan Curtin)

Google Apps Scripts web services

Google Apps Scripts for conveniently exploring melting

point data

Straight chain carboxylic acids from 1 to 10 carbons

Straight chain alcohols from 1 to 10 carbons

Comparison of model with triple validated measurements

Cyclic primary amines from 3 to 6 carbons (cyclobutylamine flagged for validation – only single source available)

Google Apps Scripts for planning reactions and creating schemes

Open Melting Points in Supplementary Data Pages of Wikipedia (Martin Walker)

All ONS web services

Some Initiatives Promoting More Openness in Drug Discovery

Open Primary Research in Drug Design using Web2.0 tools (malaria)

(blogs, wikis, Second Life, mailing lists)

Docking

Synthesis

Testing

Rajarshi GuhaIndiana U

JC BradleyDrexel U

Phil RosenthalUCSF

(malaria)

Dan ZaharevitzNCI

(tumors)

Tsu-Soo TanNanyang Inst.

Outcome of Guha-Bradley-Rosenthal collaboration

Conclusions

• For science to progress quickly there is great benefit in moving away from a “trusted source” model to one based on transparency and data provenance

• Open Notebook Science can be a useful tool in this context