This paper describes methods for modelling two enzyme families, flavin-containing monoxygenases (FMOs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs), to predict reactivity to drug metabolism. It builds on the metabolism modelling methods within the StarDrop™ P450 module now replaced by the Metabolism module.
There are several enzyme families involved throughout the drug metabolism process. These include flavin-containing monooxygenases (FMOs), which can catalyse oxidation reactions during the modification phase of drug metabolism, and uridine 5′-diphospho-glucuronosyltransferases (UGTs), the most important class of drug conjugation enzymes. UGTs catalyse glucuronidation reactions.
In this work, the team shares a study of the rate limiting steps of product formation for FMOs and UGTs, based on density functional theory calculations. They build models to calculate the activation energy of the rate-limiting steps for FMO oxidation and UGT glucuronidation at potential sites of metabolism on a compound, validated with experimental data.
M. Öeren, P. J. Walton, P. A. Hunt, D. J. Ponting, M. D. Segall, J. Comput.-Aided Mol. Des., 2021, 35(4) pp. 541-555. DOI: 10.1007/s10822-020-00321-1
This paper describes the prediction of the regioselectivity of metabolism by AOs, FMOs and UGTs for humans and CYPs for three preclinical species.
This paper describes a model to predict whether a particular site on a molecule will be metabolised by cytosolic sulfotransferase enzymes (SULTs).
Introduction Predicting sites of metabolism (SoM) enable chemists to be more efficient in optimising the structure of new chemical entities…
Watch Optibrium CEO Matt Segall and Principal Scientist Mario Öeren as they explore groundbreaking new quantum mechanics and machine learning models which go beyond P450s and provide insights on a broad range of enzymes involved in drug metabolism.
