The conversion of IUPAC's compilations of pKas of organic acids and bases into

substructure-searchable data

Tony SlaterpKaData Limited

EuroCUP III Toledo April 2009

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

www.pkadata.com

An example

NN

N

NN

N

NN

N

O

NN

N

SN

tuning the pKa of guanidine to affect some of the properties listed in the previous slide

13.6 10.8 8.3 6.8

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. PerrinDissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, by D. D. PerrinDissociation Constants of Organic Acids in Aqueous Solution, by G. Kortum, W. Vogel, and K. AndrussowIonisation 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

www.pkadata.com

pKa measurements for almost 12000 compounds in aqueous solutionnumber of measurements considerably higher (eg. some compounds have had their pKa(s) measured at different temperatures and by different authors)fully referencedmeasurement method recordedtemperature recordedremarks field provides more details such as ionic strength, buffer composition etcassessment of data quality is made

What’s special about the IUPAC set?

"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

www.pkadata.com

Range of organic chemistry includes :-

BASESaliphaticalicyclicaromaticheterocyclicnatural productsdyes and indicators

ACIDS aliphatic carboxylic acids alicyclic carboxylic acids aromatic carboxylic acids phenolic acids other acids dyes and indicators unclassified organic acids

www.pkadata.com

Range of Chemistry and Applicability

with applicability to :-

Pharmaceutical industryAgrochemical industrySpecialty Chemicals industrypKa prediction software companies

Nb. quality assessment of particular relevance here

Conversion of the Books into Data

convert names to smiles

supply full reference

translate quality assessmentinto confidence limits

supply details of method

assign data and text to relevant fields

assign temperature to correct field and put other text (eg. ~ or >) in separate field

convert pKb into pKa

assign non-numeric text (eg. <) to separate field,also assign ion group

www.pkadata.com

Some conversion “challenges”

SMILES3-bromo-Aniline okay but try these at speed :-

2,3,4,4a,9,9a-hexahydro-2-methyl-9-phenyl-1H-Indeno[2,1-c]pyridine2-dimethylamino-6,7,8,9-tetrahydro-1(3)H-Naphth[1,2-d]imidazoleMesobiliviolin

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.

www.pkadata.com

Types of Search

SubstructureSearch for basic pKa with 6.5 < pKa < 7.5Search for only highest quality dataSearch for data where 35°C ≤ temperature ≤ 40°CAny combination of the aboveEtc.................

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.

www.pkadata.com

Summarywww.pkadata.com

ContactsEmail : tony@pkadata.comWebsite : www.pkadata.com

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