Integrating Crystallography into Early Metabolism Studies

Cruciani, Gabriele; Aristei, Yasmin; Goracci, Laura; Carosati, Emanuele

doi:10.1007/978-90-481-2339-1_5

Cited by 1 publication

(1 citation statement)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The site of metabolism (SOM) refers to the site of a molecule where a metabolic reaction occurs [3]. In many cases, SOMs are determined as atoms in a molecule that are modified by enzymes (mostly by P450s) [4].…”

Section: Introductionmentioning

confidence: 99%

Prediction of reacting atoms for the major biotransformation reactions of organic xenobiotics

et al. 2016

View full text Add to dashboard Cite

BackgroundThe knowledge of drug metabolite structures is essential at the early stage of drug discovery to understand the potential liabilities and risks connected with biotransformation. The determination of the site of a molecule at which a particular metabolic reaction occurs could be used as a starting point for metabolite identification. The prediction of the site of metabolism does not always correspond to the particular atom that is modified by the enzyme but rather is often associated with a group of atoms. To overcome this problem, we propose to operate with the term “reacting atom”, corresponding to a single atom in the substrate that is modified during the biotransformation reaction. The prediction of the reacting atom(s) in a molecule for the major classes of biotransformation reactions is necessary to generate drug metabolites.ResultsSubstrates of the major human cytochromes P450 and UDP-glucuronosyltransferases from the Biovia Metabolite database were divided into nine groups according to their reaction classes, which are aliphatic and aromatic hydroxylation, N- and O-glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation. Each training set consists of positive and negative examples of structures with one labelled atom. In the positive examples, the labelled atom is the reacting atom of a particular reaction that changed adjacency. Negative examples represent non-reacting atoms of a particular reaction. We used Labelled Multilevel Neighbourhoods of Atoms descriptors for the designation of reacting atoms. A Bayesian-like algorithm was applied to estimate the structure–activity relationships. The average invariant accuracy of prediction obtained in leave-one-out and 20-fold cross-validation procedures for five human isoforms of cytochrome P450 and all isoforms of UDP-glucuronosyltransferase varies from 0.86 to 0.99 (0.96 on average).ConclusionsWe report that reacting atoms may be predicted with reasonable accuracy for the major classes of metabolic reactions—aliphatic and aromatic hydroxylation, N- and O-glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation. The proposed method is implemented as a freely available web service at http://www.way2drug.com/RA and may be used for the prediction of the most probable biotransformation reaction(s) and the appropriate reacting atoms in drug-like compounds.Graphical abstract. Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-016-0183-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%