modeling melting points

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Presentation to ORU College of Science and Engineering - November 27, 2012

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  • http://usefulchem.wikispaces.com/D-EXP022From a library of derivatives, it was the hop hit for the docking site of taxol
  • modeling melting points

    1. 1. Andrew LangProfessor of Mathematics Oral Roberts University
    2. 2. Open DrugDiscovery forNeglectedDiseasesMalariaSchistosomiasisGram positive bacteriaBreast Cancer
    3. 3. Drugs for neglected diseases need to be…
    4. 4. cheap and…
    5. 5. easy to make.
    6. 6. combinatorial librarysolubility data docking solubility models synthesis solvent selection biological recrystallization assaymelting point modelsmelting point The big picture data
    7. 7. combinatorial librarysolubility data docking solubility models synthesis solvent selection biological recrystallization assaymelting point modelsmelting point Oral Roberts University data undergraduate research
    8. 8. David Bulger MD/PhD Student TennesseeCameron Neylon Solubility Measurements and UgiBiophysicist 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
    9. 9. Lacey Condron Chemistry Major Lizzie ClarkNursing Major Samantha Gaines, Lizzie Clark, and Lacey Condron Solubility Measurements and Solubility Modeling at ORU Supervisors: Ken Weed, Lois Ablin
    10. 10. Daryl Charron, Alejandro Hernandez, Maria Hernandez, Jesse Patsolic, Matthew WilsonCluster Computer Construction and In-Silico Docking at ORU Supervisors: Ken Preston
    11. 11. combinatorial librarysolubility data docking solubility models synthesis solvent selection biological recrystallization assaymelting point modelsmelting point Let’s focus data
    12. 12. Early models, before 2005 were…
    13. 13. …specialized1979 Martin – disubstituted benzenes1987 Hanson – normal alkanes1988 Needham – normal and branched alkanes1990 Abramowitz – non-hydrogen bonded benzenes1991 Dearden – anilines1993 Katritzky – aldehydes, amines, and ketones1994 Simamora – rigid aromatic1996 Charlton – alkanes1996 Katritzky – pyridines1999 Zhao – aliphatic2001 Chickos – homologous series2003 Bergstrom – druglike (N = 277, r2 = 0.54)
    14. 14. In 2005… …everything changed
    15. 15. MDPI - cheminformatics.orgKarthikeyan 2005 N = 4173, r2 = 0.65
    16. 16. PHYSPROPClark 2005 N = 6257, r2 = 0.61
    17. 17. Recent melting point models use these datasets……never reproducing r2 = 0.65 (0.47 – 0.56)
    18. 18. Even though [a] melting pointcan be measured accurately, itsprediction has been anotoriously difficult problem.
    19. 19. We beganmeasuring, collecting, andcurating melting points in the
    20. 20. Jean-Claude Bradley’s Chemical Information Retrieval Course at Drexel567 curated and referenced measurements fromFall 2010 Chemical Information Retrieval course
    21. 21. Most popular data sources… …chemical vendors
    22. 22. Alfa Aesar donates ~13,000melting points to the public domain
    23. 23. collectionmeasurement curation ONS melting point workflow validation modeling
    24. 24. Collection: Open Datasource data points curated values source year data typeBell 2483 1631 1995 donated-CC0Bergstrom 277 277 2003 openMDPI-Karthikeyan 4450 4084 2005 openHughes 287 262 2008 openOxford-MSDS 3217 1481 2010 openDrugbank 875 875 2011 openGriffiths 3757 278 2011 donated-CC0Alfa Aesar 12986 8739 2011 donated-CC0PHYSPROP 11645 9694 2011 donated-CC0ONS 471 471 2012 open 27792 curated measurements for 19410 compounds
    25. 25. Antony Williams – RSC ChemSpider Curation is……lots of hard, tedious work(Jean-Claude Bradley and Antony Williams)
    26. 26. Inconsistencies and SMILES problemswithin the “high trust level” MDPI dataset
    27. 27. PHYSPROP Structure Errors (Incorrect Valence)2315 out of 43543 contained pentavalent nitrogens
    28. 28. PHYSPROP Errors: Structure displayed is for the neutralcompound dopamine but the associated CAS Number and chemical name in the file are for the hydrobromide salt.
    29. 29. unit errors: Kelvin/Celsius, Fahrenheit/Celsiusbad SMILES (non-rendering, hypervalency)salts associated with SMILES for free baseusing boiling point for melting point
    30. 30. Some melting points can’t be resolved only with literature: 4-benzyltoluene
    31. 31. Open lab notebook pagemeasuring the melting point of 4-benzyltoluene
    32. 32. CDK descriptor calculator R statistical computing Meltingmelting point data Point Model
    33. 33. use this model
    34. 34. compounds CDKdoubleplusgood descriptor calculatorsingle R statistical computing Melting Point Model
    35. 35. Comparison of model withdouble+ validated measurementsStraight chain carboxylic acids from 1 to 10 carbons Straight chain alcohols from 1 to 10 carbons
    36. 36. Cyclic primary amines from 3 to 6 carbonscyclobutylamine flagged for measurement only single source available
    37. 37. Publication of double+ validated melting point dataset …as a preprint
    38. 38. Publication of double+ validated melting point dataset …as a book
    39. 39. Data and model deployed… web service …on the web
    40. 40. …in Google spreadsheets
    41. 41. …as an app
    42. 42.  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]
    43. 43.  First recrystallized in ethyl acetate in 1906: Straus and Ecker, Ber. 39, 2988 (1906) Recrystallized in ethyl acetate in Organic Syntheses
    44. 44.  Recommended recrystallization solvent: ethyl acetate. (http://classes.kvcc.edu/chm230/mixed%20aldol%20condensation.pdf (http://www.xula.edu/chemistry/documents/orgleclab/Aldol_notes.pdf)
    45. 45. Enter compound identification and desired parameters
    46. 46. How does it work?1. Look up the solvent boiling point2. Look up the room temperature solubility or predict it via measured orpredicted Abraham descriptors3. Look up the solute melting point or predict it via a model4. Use the melting point and the solubility at room temperature to predictthe solubility at boiling5. Calculate the predicted recrystallization yield
    47. 47. Lists solvents and their predicted recrystallization yield.Prediction is generated by the temperature dependentsolubility curves.
    48. 48.  ethyl acetate (predicted yield of 72%) vs ethanol (predicted yield of 93%) ethyl acetate 2.06M 0.62M ethanol 1.1M 0.09M
    49. 49. Dibenzalacetone derivatives docking against tubulin (paclitaxel site)
    50. 50.  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
    51. 51.  Perform a Reaxys search to determine availability of synthesis procedures No results [Matthew McBride: Undergraduate Research Assistant - Drexel]
    52. 52. (http://usefulchem.wikispaces.com/EXP286) Used methanol and benzene Melting Point: 264-265 C [Matthew McBride: Undergraduate Research Assistant - Drexel]
    53. 53. AcknowledgementsORU Biology and Chemistry FacultyJean-Claude Bradley (Drexel)Cameron Neylon (RAL)Antony Williams (RSC ChemSpider)Evan Curtin (Drexel)Matthew McBride (Drexel)ORU research assistants: David Bulger, DarylCharron, Lizzie Clark, Lacey Condron, SamanthaGaines, Alejandro Hernandez, Maria Hernandez, JessePatsolic, and Matthew Wilson
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