Eli Lilly MedChem Rules.

This MedChem rules is a set of 275 rules, developed over an 18-year period at Lilly and used to identify compounds that may interfere with biological assays, allowing their removal from screening sets. Reasons for rejection include reactivity (e.g., acyl halides), interference with assay measurements (fluorescence, absorbance, quenching), activities that damage proteins (oxidizers, detergents), instability (e.g., latent aldehydes), and lack of druggability (e.g., compounds lacking both oxygen and nitrogen).
The structural queries were profiled for frequency of occurrence in druglike and nondruglike compound sets and were extensively reviewed by a panel of experienced medicinal chemists. As a means of profiling the rules and as a filter in its own right, an index of biological promiscuity was developed. Because this type of interference is not amenable to substructure search, a "nuisance list" was developed to flag interfering compounds that passed the substructure rules.
Three versions of the rules were used in the profiling:

  • outright rejections computed without the demerit rules (nodemerit in FAFDrugs4 where only hard rejections are applied).
  • relaxed rules with a 160-demerit cutoff (relaxed).
  • regular rules with a 100-demerit cutoff (regular).

In the seminal publication, authors explained that the rules were used to filter primary and follow-up screensets, to triage compounds being considered for purchase, and as alerts for compounds being proposed for synthesis.

Software and queries are available at https://github.com/IanAWatson/Lilly-Medchem-Rules.git or from watson_ian_a@lilly.com.

Bruns et al, J. Med. Chem, 2012 [53]