Predicting routes of phase I and II metabolism based on quantum mechanics and machine learning.

Unexpected metabolism could lead to the failure of many late-stage drug candidates or even the withdrawal of approved drugs. Thus, it is critical to predict and study the dominant routes of metabolism in the early stages of research.We describe the development and validation of a 'WhichEnzyme' model that accurately predicts the enzyme families most likely to be responsible for a drug-like molecule's metabolism.

Predicting Regioselectivity of Cytosolic Sulfotransferase Metabolism for Drugs.

Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation of small endogenous and exogenous compounds. SULTs contribute to the conjugation phase of metabolism and share substrates with the uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes. UGTs are considered to be the most important enzymes in the conjugation phase, and SULTs are an auxiliary enzyme system to them.

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

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.

Predicting reactivity to drug metabolism: beyond P450s-modelling FMOs and UGTs.

We present a study based on density functional theory calculations to explore the rate limiting steps of product formation for oxidation by Flavin-containing Monooxygenase (FMO) and glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes. FMOs are responsible for the modification phase of metabolism of a wide diversity of drugs, working in conjunction with Cytochrome P450 (CYP) family of enzymes, and UGTs are the most important class of drug conjugation enzymes. Reactivity calculations are important for prediction of metabolism by CYPs and reactivity alone explains around 70-85% of the experimentally observed sites of metabolism within CYP substrates.

WhichP450: a multi-class categorical model to predict the major metabolising CYP450 isoform for a compound.

In the development of novel pharmaceuticals, the knowledge of how many, and which, Cytochrome P450 isoforms are involved in the phase I metabolism of a compound is important. Potential problems can arise if a compound is metabolised predominantly by a single isoform in terms of drug-drug interactions or genetic polymorphisms that would lead to variations in exposure in the general population. Combined with models of regioselectivities of metabolism by each isoform, such a model would also aid in the prediction of the metabolites likely to be formed by P450-mediated metabolism.

Predicting Regioselectivity and Lability of Cytochrome P450 Metabolism Using Quantum Mechanical Simulations.

We describe methods for predicting cytochrome P450 (CYP) metabolism incorporating both pathway-specific reactivity and isoform-specific accessibility considerations. Semiempirical quantum mechanical (QM) simulations, parametrized using experimental data and ab initio calculations, estimate the reactivity of each potential site of metabolism (SOM) in the context of the whole molecule. Ligand-based models, trained using high-quality regioselectivity data, correct for orientation and steric effects of the different CYP isoform binding pockets.

Aminoalkyl phenyl sulfones--a novel series of 5-HT7 receptor ligands.

A novel series of 5-HT(7) receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.

Multiple structural features of steroids mediate subtype-selective effects on human alpha4beta3delta GABAA receptors.

Neurosteroids have been shown to mediate some of their physiological effects via a modulatory site on type A inhibitory gamma-aminobutyric acid (GABAA) receptors. In particular, recent evidence has implicated selective potentiation of the delta subunit of GABAA receptors as an important mediator of in vitro and in vivo neurosteroid activity. However, this has been demonstrated for only a very small number of steroids, so both the generality of this finding, and the structural features of steroids which mediate functional delta-selectivity, are unclear.