In several recent posts1,2 we highlighted the usefulness of an expert review of potentially reactive features. This is particularly important when an out-of-domain result is returned or when an area of the test chemical is not being considered by the computational model. The US Food and Drug Administration (FDA) recently published a paper showing that expert knowledge plays an important role in increasing the reliability of (Q)SAR predictions3. Software to support various expert review methodologies is needed to facilitate thorough computational assessments.  

Examining how often different substructural features present in the test chemical appear in historical collections of chemicals with experimental results will tell us whether such a feature is potentially problematic (i.e., there are more toxic examples than you would generally expect) or whether there is no concern (i.e., the proportion of toxic chemicals is either similar to or less than the proportion observed in the whole database). The blog “The use of chemical analogs in expert reviews”2 includes some nice examples.

The Leadscope products make use of a dictionary of over 27,000 substructural fragments often described as the ‘Leadscope feature hierarchy’4. Matching any of these predefined structural features, that are also present in your test chemical, against a database is a great starting point. However, there may still be questions about specific chemical fragments that are not included in this list.

Over the last year, we have been working hard to implement a brand-new chemical structure drawing package which is being integrated into the Leadscope tools. Although one of the more common applications of this tool will be to draw a chemical structure on which to apply computational models, the tool is also ideal for the assessment of ad hoc potentially reactive features.

Please get in touch with me (Glenn Myatt, glenn.myatt@instem.com) if you would like to discuss this approach in more detail.

References

  1. How an expert-review could be used to resolve out-of-domains
  2. The use of chemical analogs in expert reviews
  3. Jayasekara, S et al., Assessing the impact of expert knowledge on ICH M7 (Q)SAR predictions. Is expert review still needed?, Regulatory Toxicology and Pharmacology, 125,  2021, 105006
  4. Roberts G, et al., Leadscope: Software for Exploring Large Sets of Screening Data. J. Chem. Inf. Comput. Sci., 2000, 40, 1302-1314.

Published by Glenn Myatt

Glenn J. Myatt is the co-founder of Leadscope and currently Senior Vice President, In Silico & Translational Science Solutions at Instem with over 25 years’ experience in computational chemistry/toxicology. He holds a Bachelor of Science degree in Computing, a Master of Science degree in Artificial Intelligence and a Ph.D. in Chemoinformatics. He has published 34 papers, 10 book chapters and three books.