In the PAINS/Tox tab, the user can create a PAINS/Tox filter for a list of SMARTS that should not be considered during the generation.
To create a new PAINS/Tox filter, click on the New PAINS/Tox dictionary box. On the following page, specify a name for this object and upload a CSV file that contains the unwanted SMARTS. The CSV file should be a single-column file and a list of the unwanted SMARTS. Finally, click on the Create PAINS/Tox button.
Default PAINs/Tox filters
Fine-Tuning Generator
Molecules generated in Makya using the Fine-Tuning generator are automatically filtered so as to reject some structures that are known to be associated with unwanted molecules. The filtered substructures form a default PAINs/Tox filter and come from the following dictionaries:
- PAINS - Pan assay interference patterns.
- Reference: Baell JB, Holloway GA. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays.
- BRENK - potential toxicity and unfavorable pharmacokinetics.
- Reference: Brenk R et al. Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases.
- NIH - problematic functional groups.
- References:
- Doveston R, et al. A Unified Lead-oriented Synthesis of over Fifty Molecular Scaffolds.
- Jadhav A, et al. Quantitative Analyses of Aggregation, Autofluorescence, and Reactivity Artifacts in a Screen for Inhibitors of a Thiol Protease.
- References:
We regularly update these well-known lists and add our own lists of Iktos motifs, identified from the literature or from our own projects as inducing false positive compounds, problems of selectivity, or issues with toxicity.
If the user selects a PAINS/Tox filter in the generator set-up, the default PAINS/Tox filter is not used.
Fragment Growing / Fragments Linking Generators
Makya's fragment-based generators are chemistry-driven and build molecules using building blocks sold by commercial providers for their interesting chemical properties and abilities to make drug-like molecules. As such, no default PAINS/Tox filter is implemented.