Lhasa Limited shared knowledge shared progress
Publications
  • Highlighted Item:
  • Webinar:
  • Publisher:
    2022 American Chemical Society
  • Publication Date:
    Oct 2022
  • Reference:
    Journal of Medicinal Chemistry (2022)
  • DOI:
    doi.org/10.1021/acs.jmedchem.2c01303
  • PMID:
  • Publication Type:
    Paper
  • Related Products:
  • Scientific Area:
  • Endpoint:
  • Industry Type:
  • Related event:

Predicting Regioselectivity of AO, CYP, FMO, and UGT Metabolism Using Quantum Mechanical Simulations and Machine Learning

Öeren M; Walton PJ; Suri J; Ponting DJ; Hunt PA; Segall MD;

Unexpected metabolism in modification and conjugation phases can lead to the failure of many late-stage drug candidates or even withdrawal of approved drugs. Thus, it is critical to predict the sites of metabolism (SoM) for enzymes, which interact with drug-like molecules, in the early stages of the research. This study presents methods for predicting the isoform-specific metabolism for human AOs, FMOs, and UGTs and general CYP metabolism for preclinical species. The models use semi-empirical quantum mechanical simulations, validated using experimentally obtained data and DFT calculations, to estimate the reactivity of each SoM in the context of the whole molecule. Ligand-based models, trained and tested using high-quality regioselectivity data, combine the reactivity of the potential SoM with the orientation and steric effects of the binding pockets of the different enzyme isoforms. The resulting models achieve ? values of up to 0.94 and AUC of up to 0.92.

Visit site

© 2023 Lhasa Limited | Registered office: Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK Tel: +44 (0)113 394 6020
VAT number 396 8737 77 | Lhasa Limited is registered as a charity (290866)| Company Registration Number 01765239 (England and Wales).