The bioactivation of drugs may result in the generation of reactive metabolites that irreversibly inactivate cytochrome P450 (requiring synthesis of new enzyme for recovery of activity). This process is referred to as mechanism-based inhibition (MBI) or time-dependent inhibition and is often involved in damaging drug-drug interactions (DDIs).

Within the FDA guidance “In Vitro Drug Interaction Studies – Cytochrome P450 (CYP) Enzyme- and Transporter-Mediated Drug Interactions guidance”, structural alerts associated with MBI may be used to support the selection of in vitro CYP enzyme inhibition studies to help understand DDIs.1 To support this in silico assessment, we compiled a series of structural alerts (based on over 700 unique substructure searches) associated with bioactivation leading to MBI of P450. These alerts have been incorporated within the Leadscope model applier to profile a substance and provide information on the underlying MBI pathways.

A recent poster at the American College of Toxicology 2021 meeting provided an overview of this approach, alongside a discussion of the preliminary qualification of these alerts using proprietary data.2

We are currently collaborating with a number of organizations to use additional proprietary data to qualify and refine the current alerts, as well as to identify additional alerts. This is based on a SAR-fingerprint approach3 whereby knowledge of structure-activity relationships is shared without disclosing any information on proprietary chemicals or study data. We are looking to publish the results and document the improved predictivity.

If you are interested in collaborating on this project, or would like a copy of the recent poster, please get in touch with me (Glenn Myatt; glenn.myatt@instem.com).

References

  1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
  2. Bassan, A., Selvam, R., Bower, D., Cross, K.P., Stavitskaya, L., Yang, X., Volpe D.A., Amberg, A., Myatt, G.J., 2021. Development of a structure activity relationship profiler to predict mechanism based inhibition of a metabolite on CYP enzymes. Presented at the ACT Virtual 42nd Annual Meeting.
  3. Ahlberg, E., Amberg, A., Beilke, L.D., Bower, D., Cross, K.P., Custer, L., Ford, K.A., Gompel, J.V., Harvey, J., Honma, M., Jolly, R., Joossens, E., Kemper, R.A., Kenyon, M., Kruhlak, N., Kuhnke, L., Leavitt, P., Naven, R., Neilan, C., Quigley, D.P., Shuey, D., Spirkl, H.-P., Stavitskaya, L., Teasdale, A., White, A., Wichard, J., Zwickl, C., Myatt, G.J., 2016. Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity. Regulatory Toxicology and Pharmacology 77, 1–12. doi:10.1016/j.yrtph.2016.02.003 

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 30 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 37 papers, 11 book chapters and three books.