Map PAINS substructures according to PAINS class and find the highest PAINS violation

Many scientists are unaware that PAINS substructures are classified by hit frequency; this has led to a tendency to irresponsibly use PAINS filters during compound triage by filtering out potential leads based on the presence of a PAINS substructure instead of the presence of a type of PAINS substructure. Baell suggested in his review, Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017 - Utility and Limitations, that scientists should focus on class A, maybe class B, and not class C. Because the original paper only reported hit frequency based on a singular assay technology, compounds should not be necessarily excluded for containing a class A substructure.

This protocol splits the different classes of PAINS into distinct substructure mapping subprotocols to produce a more informed PAINS report.

The SMARTS patterns can be obtained here.

This protocol is being made available in conjunction with an upcoming publication.

Methods
Please refer to Materials and Methods and Supplementary Material of the associated manuscript, Small molecule inhibitors of the human recombination-associated ATPase, RAD54.