This document describes open drug discovery research being conducted at Oral Roberts University to measure and model compound solubility and melting points in order to design drugs for neglected diseases; it provides an overview of undergraduate research assistants involved in various aspects of the project such as solubility measurements, computer modeling, and synthesis under the supervision of professors from ORU, Drexel, and RAL.

1. Andrew Lang
Professor of Mathematics
Oral Roberts University

3. Open Drug
Discovery for
Neglected
Diseases
Malaria
Schistosomiasis
Gram positive bacteria
Breast Cancer

4. Drugs for neglected diseases
need to be…

5. cheap and…

6. easy to make.

7. combinatorial
library
solubility data
docking
solubility
models
synthesis
solvent
selection
biological
recrystallization
assay
melting point
models
melting point The big picture
data

8. combinatorial
library
solubility data
docking
solubility
models
synthesis
solvent
selection
biological
recrystallization
assay
melting point
models
melting point
Oral Roberts University
data
undergraduate research

9. David Bulger
MD/PhD Student
Tennessee
Cameron Neylon Solubility Measurements and Ugi
Biophysicist RAL Product Synthesis at ORU,
Drexel, and RAL
Submeta ONS Award Winner,
BOE Award Winner
Supervisors: Robert Stewart, Lois
Ablin, Bill Collier, Joel Gaikwad,
Jean-Claude Bradley, and
Cameron Neylon

10. Lacey Condron
Chemistry Major
Lizzie Clark
Nursing Major
Samantha Gaines, Lizzie
Clark, and Lacey Condron
Solubility Measurements and
Solubility Modeling at ORU
Supervisors: Ken Weed, Lois Ablin

11. Daryl Charron, Alejandro
Hernandez, Maria
Hernandez, Jesse
Patsolic, Matthew Wilson
Cluster Computer Construction
and In-Silico Docking at ORU
Supervisors: Ken Preston

12. combinatorial
library
solubility data
docking
solubility
models
synthesis
solvent
selection
biological
recrystallization
assay
melting point
models
melting point Let’s focus
data

13. Early models, before 2005 were…

14. …specialized
1979 Martin – disubstituted benzenes
1987 Hanson – normal alkanes
1988 Needham – normal and branched alkanes
1990 Abramowitz – non-hydrogen bonded benzenes
1991 Dearden – anilines
1993 Katritzky – aldehydes, amines, and ketones
1994 Simamora – rigid aromatic
1996 Charlton – alkanes
1996 Katritzky – pyridines
1999 Zhao – aliphatic
2001 Chickos – homologous series
2003 Bergstrom – druglike (N = 277, r2 = 0.54)

15. In 2005…
…everything changed

16. MDPI - cheminformatics.org
Karthikeyan 2005 N = 4173, r2 = 0.65

17. PHYSPROP
Clark 2005 N = 6257, r2 = 0.61

18. Recent melting point models
use these datasets…
…never reproducing r2 = 0.65 (0.47 – 0.56)

19. Even though [a] melting point
can be measured accurately, its
prediction has been a
notoriously difficult problem.

20. We began
measuring, collecting, and
curating melting points in the

21. Jean-Claude Bradley’s
Chemical Information Retrieval
Course at Drexel
567 curated and referenced measurements from
Fall 2010 Chemical Information Retrieval course

22. Most popular data sources…
…chemical vendors

23. Alfa Aesar donates ~13,000
melting points to the public domain

24. collection
measurement curation
ONS
melting point
workflow
validation modeling

25. Collection: Open Data
source data points curated values source year data type
Bell 2483 1631 1995 donated-CC0
Bergstrom 277 277 2003 open
MDPI-Karthikeyan 4450 4084 2005 open
Hughes 287 262 2008 open
Oxford-MSDS 3217 1481 2010 open
Drugbank 875 875 2011 open
Griffiths 3757 278 2011 donated-CC0
Alfa Aesar 12986 8739 2011 donated-CC0
PHYSPROP 11645 9694 2011 donated-CC0
ONS 471 471 2012 open
27792 curated measurements
for 19410 compounds

26. Antony Williams – RSC ChemSpider
Curation is…
…lots of hard, tedious work
(Jean-Claude Bradley and Antony Williams)

27. Inconsistencies and SMILES problems
within the “high trust level” MDPI dataset

28. PHYSPROP Structure Errors (Incorrect Valence)
2315 out of 43543 contained pentavalent nitrogens

29. PHYSPROP Errors: Structure displayed is for the neutral
compound dopamine but the associated CAS Number and
chemical name in the file are for the hydrobromide salt.

30. unit errors: Kelvin/Celsius, Fahrenheit/Celsius
bad SMILES (non-rendering, hypervalency)
salts associated with SMILES for free base
using boiling point for melting point

31. Some melting points can’t be resolved
only with literature: 4-benzyltoluene

32. Open lab notebook page
measuring the melting point of 4-benzyltoluene

33. CDK
descriptor calculator
R
statistical computing
Melting
melting point data Point
Model

34. use this model

35. compounds CDK
doubleplusgood descriptor calculator
single
R
statistical computing
Melting
Point
Model

37. Comparison of model with
double+ validated measurements
Straight chain carboxylic acids from 1 to 10 carbons
Straight chain alcohols from 1 to 10 carbons

38. Cyclic primary amines from 3 to 6 carbons
cyclobutylamine flagged for measurement
only single source available

39. Publication of double+ validated
melting point dataset
…as a preprint

40. Publication of double+ validated
melting point dataset
…as a book

41. Data and model deployed…
web service
…on the web

42. …in Google spreadsheets

43. …as an app

44.  Can the solvents used to recrystallize compounds in
organic teaching labs be improved?
 Trans-dibenzalacetone
 Aldol condensation between two molecules of
benzaldehyde and one molecule of acetone
[Matthew McBride: Undergraduate Research Assistant - Drexel]

45.  First recrystallized in ethyl acetate in 1906: Straus
and Ecker, Ber. 39, 2988 (1906)
 Recrystallized in ethyl acetate in Organic Syntheses

46.  Recommended recrystallization solvent: ethyl acetate.
(http://classes.kvcc.edu/chm230/mixed%20aldol%20condensation.pdf
(http://www.xula.edu/chemistry/documents/orgleclab/Aldol_notes.pdf)

47. Enter compound identification and desired parameters

48. How does it work?
1. Look up the solvent boiling point
2. Look up the room temperature solubility or predict it via measured or
predicted Abraham descriptors
3. Look up the solute melting point or predict it via a model
4. Use the melting point and the solubility at room temperature to predict
the solubility at boiling
5. Calculate the predicted recrystallization yield

49. Lists solvents and their predicted recrystallization yield.
Prediction is generated by the temperature dependent
solubility curves.

50.  ethyl acetate (predicted yield of 72%) vs ethanol
(predicted yield of 93%)
 ethyl acetate 2.06M
0.62M
 ethanol 1.1M
0.09M

51. Dibenzalacetone derivatives docking against tubulin
(paclitaxel site)

52.  Derivatives of dibenzalacetone may be synthesized
by altering the aldehyde used
 From a library of derivatives, the following
compound was the top hit for the docking site of
Taxol
 Uses phenanthrene-9-carboxaldehyde

53.  Perform a Reaxys search to determine availability
of synthesis procedures
 No results
[Matthew McBride: Undergraduate Research Assistant - Drexel]

54. (http://usefulchem.wikispaces.com/EXP286)
 Used methanol and benzene
 Melting Point: 264-265 C
[Matthew McBride: Undergraduate Research Assistant - Drexel]

55. Acknowledgements
ORU Biology and Chemistry Faculty
Jean-Claude Bradley (Drexel)
Cameron Neylon (RAL)
Antony Williams (RSC ChemSpider)
Evan Curtin (Drexel)
Matthew McBride (Drexel)
ORU research assistants: David Bulger, Daryl
Charron, Lizzie Clark, Lacey Condron, Samantha
Gaines, Alejandro Hernandez, Maria Hernandez, Jesse
Patsolic, and Matthew Wilson