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The conversion of IUPAC's compilations of pKas of organic acids and bases into substructure-searchable data

www.pkadata.com. The conversion of IUPAC's compilations of pKas of organic acids and bases into substructure-searchable data. Tony Slater pKaData Limited. EuroCUP III Toledo April 2009. www.pkadata.com. Why the interest in pKas?. The extent of ionisation of a drug can control :-

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The conversion of IUPAC's compilations of pKas of organic acids and bases into substructure-searchable data

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  1. www.pkadata.com The conversion of IUPAC's compilations of pKas of organic acids and bases into substructure-searchable data Tony Slater pKaData Limited EuroCUP III Toledo April 2009

  2. www.pkadata.com Why the interest in pKas? The extent of ionisation of a drug can control :- • strength of interaction with receptor • protein binding • absorption • distribution • metabolism • elimination • solubility • dissolution rate

  3. www.pkadata.com An example tuning the pKa of guanidine to affect some of the properties listed in the previous slide 6.8 13.6 10.8 8.3

  4. www.pkadata.com The IUPAC compilation Four books containing pKa data for organic acids and bases in aqueous solution :- • Dissociation Constants of Organic Bases in Aqueous Solution, by D. D. Perrin • Dissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, by D. D. Perrin • Dissociation Constants of Organic Acids in Aqueous Solution, by G. Kortum, W. Vogel, and K. Andrussow • Ionisation Constants of Organic Acids in Aqueous Solution, by E. P. Serjeant and Boyd Dempsey One book containing pKa data for organic acids and bases in non-aqueous solution :- • Acid-Base Dissociation Constants in Dipolar Aprotic Solvents (1990); K. Izutsu

  5. www.pkadata.com What’s special about the IUPAC set? • pKa measurements for almost 12000 compounds in aqueous solution • number of measurements considerably higher (eg. some compounds have had their pKa(s) measured at different temperatures and by different authors) • fully referenced • measurement method recorded • temperature recorded • remarks field provides more details such as ionic strength, buffer composition etc • assessment of data quality is made "The critical assessment of data quality is one of the major features of this seminal group of pKa compilations for weak organic acids and bases sponsored by the International Union of Pure and Applied Chemistry (IUPAC)“ from Profiles of Drug Substances, Excipients and Related Methodology Volume 33, 2007, by Richard J. Prankerd, ed Harry G. Brittain

  6. www.pkadata.com Range of Chemistry and Applicability Range of organic chemistry includes :- BASES aliphatic alicyclic aromatic heterocyclic natural products dyes and indicators • ACIDS • aliphatic carboxylic acids • alicyclic carboxylic acids • aromatic carboxylic acids • phenolic acids • other acids • dyes and indicators • unclassified organic acids • with applicability to :- • Pharmaceutical industry • Agrochemical industry • Specialty Chemicals industry • pKa prediction software companies • Nb. quality assessment of particular relevance here

  7. www.pkadata.com Conversion of the Books into Data assign data and text to relevant fields supply full reference supply details of method convert pKb into pKa convert names to smiles translate quality assessment into confidence limits assign non-numeric text (eg. <) to separate field, also assign ion group assign temperature to correct field and put other text (eg. ~ or >) in separate field

  8. www.pkadata.com Some conversion “challenges” SMILES 3-bromo-Aniline okay but try these at speed :- • 2,3,4,4a,9,9a-hexahydro-2-methyl-9-phenyl-1H-Indeno[2,1-c]pyridine • 2-dimethylamino-6,7,8,9-tetrahydro-1(3)H-Naphth[1,2-d]imidazole • Mesobiliviolin need to do some research to identify some of the structures If it takes ~ 5 minutes to convert each name into a smiles, then working for 5 hours each day, 5 days a week, with some time off for good behaviour, will require almost a year to produce 12000 smiles.

  9. www.pkadata.com Types of Search • Substructure • Search for basicpKa with 6.5 < pKa < 7.5 • Search for only highest quality data • Search for data where 35°C ≤ temperature ≤ 40°C • Any combination of the above • Etc................. We only supply the data, in suitable format, not the search software, so the types of search possible will depend on your in-house software. This also means that these IUPAC pKa data can be merged with your existing in-house data, with the IUPAC-sourced data clearly identified.

  10. www.pkadata.com Summary • IUPAC pKa compilations as computer-readable data • pKa data for ~12000 organic acids and bases in aqueous solution • Very careful assignment of smiles to names by one person • Good range of organic chemistry with applicability to pharmaceutical, • agrochemical and specialty chemicals research • IUPAC assignment of data quality • Very useful data set for pKa prediction software • Fully referenced with method, temperature, ionic strength etc recorded • Careful numeric field assignment for greater search flexibility • Ion group assignment for logD calculations and greater search capability • Ability to merge with existing in-house data, with IUPAC-sourced data • clearly identified Contacts Email : tony@pkadata.com Website : www.pkadata.com

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