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Tales from the war on error: the art and science of curating QSAR data

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Abstract

Curating the data underlying quantitative structure–activity relationship models is a never-ending struggle. Some curation can now be automated but much cannot, especially where data as complex as those pertaining to molecular absorption, distribution, metabolism, excretion, and toxicity are concerned (vide infra). The authors discuss some particularly challenging problem areas in terms of specific examples involving experimental context, incompleteness of data, confusion of units, problematic nomenclature, tautomerism, and misapplication of automated structure recognition tools.

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Notes

  1. Supplemental material provided by O’Reilly et al. [29] provides an excellent overview of how to interconvert the various types of specifications and half-life measurements.

  2. Variously attributed to Bill Vaughn and Paul Ehrlich.

  3. The particular problematic “compounds” found revealed incidental limitations in the SMILES parser used that have little practical relevance but that have since been addressed.

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Acknowledgments

The authors wish to thank Jinhua Zhang, Michael S. Lawless, Jayeeta Ghosh, and Michael Bolger for their help in ferreting out errors over the years. We also thank the Simulations Technology colleagues at Simulations Plus for their ongoing real-world testing of the models that were the ultimate product of our efforts: nothing is so effective an inducement to careful curation as knowing that the person across the hall depends on your getting it right. Thanks are also due to Ian Haworth (University of Southern California) and Terry Stouch (Science for Solutions, LLC) for the insight, inspiration, encouragement, and useful information they have provided us.

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Correspondence to Robert D. Clark.

Appendix

Appendix

Endpoint

Some things to worry about

Solubility

Units: mg/mL (ppt) versus mg/L (ppm) versus M

Temperature

Miscibility and solubility are somewhat different things

Mixed solvents

Salts & other mixtures

Ionic strength

Use of buffers without checking the final pH

Precipitation of insoluble salts (e.g., phosphates)

Melting point

Decomposition

Salts versus free acids or bases

Structures

Esters versus salts

Spelling variants

Primes & double primes in names

Synonyms

Stereoisomers

Names match but structures do not

Strange amidine and guanidine valence isomers

Inverted tetrahedral & planar trisubstituted sp3 carbons

Tautomers

Electron-deficient amidines & aminopyridines

Hydroxypyridines usually exist as pyridones

Triketones usually enolize

Amides and esters only rarely enolize

pKa

Temperature

Solvent

Ionic strength

Tautomeric representation

Multiple closely spaced pKa’s

Protonated nitro groups

Doubly protonated piperazines at physiological pH

Identification of pKa’s with specific groups may be problematic in some cases

CYP assays

Complex kinetics

Substrate inhibition

Nonstandard recombinant assay systems

Mutant isoforms

Interference from other oxidases or hydrolases

Aromatic epoxidation versus hydroxylation

Disappearance of parent versus appearance of product

CLint determinations at single substrate concentrations

UGT assays

Reactive or unstable products

Endoplasmic reticulum accessibility artifacts

In vivo metabolites

Prodrugs

Unstable or reactive metabolites

Secondary metabolites

Units

Satellite peaks in distribution near three log units away from the average

Negative log units: M versus mM versus μM

Typographical errors: “m” for “μ”

Discrepancies between units in tables and in the text

Enzyme & binding assays

IC50 versus Ki

Comparability of assay conditions

Substrate or displaced ligand identity

Substrate or displaced ligand concentration

Source of the enzyme or receptor

Limit values like “>10 μM” becoming “10.00 μM”

General

The fact that internet sources agree does not make something true

If something looks too high or too low to be true: check it out

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Waldman, M., Fraczkiewicz, R. & Clark, R.D. Tales from the war on error: the art and science of curating QSAR data. J Comput Aided Mol Des 29, 897–910 (2015). https://doi.org/10.1007/s10822-015-9865-0

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