Predicting Biotransformation Potential from Molecular Structure

Abstract

The program PASS-BioTransfo is presented, which is capable of predicting many classes of biotransformation for chemical compounds. A particular class of biotransformation is defined by the chemical transformation type and may additionally include the name of the enzyme involved in a transformation. An evaluation of the approach is presented, using biotransformations taken from the databases Metabolite (MDL) and Metabolism (Accelrys), respectively. When trained with biotransformations from Metabolite, PASS-BioTransfo predicts 1927 classes of biotransformation; the average accuracy estimated in LOO cross-validation is about 88%. After training with the biotransformations from the Metabolism database, 178 classes of biotransformation are predicted with an average accuracy of about 85%. The results of cross-prediction with several training and evaluation sets are presented and discussed.

Dearomatisation of o‐Xylene by P450BM3 (CYP102A1)

“…It is true that coupling was also efficient in the oxidation of o-xylene by variant RLYF/A330P (62 %), where no single product accounted for more than 30 % of the total, but this was because the constricted A330P active site [26] suits compact substrates, [18] while the RLYF couplet may reduce peroxide formation by mitigating active-site water levels. [8] Computational studies predicted dearomatisation as an oxidation pathway for CYP1A1, [46] but to the best of our knowledge it has not previously been reported as an experimental outcome. Relatively few substrates possess structures that render them susceptible to such rearrangements, but ortho-substituted aromatics are evidently potential candidates when oxidised by isoforms that allow limited substrate mobility.…”

Feasibility of different mass spectrometric techniques and programs for automated metabolite profiling of tramadol in human urine

“…One particular limitation of the programs is that they do not provide a comprehensive list of all theoretically possible biotransformation reactions for the drug. Computer‐based systems for the prediction of routes of drug metabolism are available and are becoming more reliable as metabolism data for different compounds is added to them but it is still not possible to fully predict the metabolism of a particular compound solely on the basis of its structure 12…”

Computational Tools And Resources For Metabolism-Related Property Predictions. 1. Overview Of Publicly Available (Free And Commercial) Databases And Software

“…It was intended to be a wide collection of metabolism data with a focus on quantity rather than quality [23] and now includes compounds from New Drug Applications, proceedings from meetings of the International Society for the Study of Xenobiotics and the scientific literature from 1990 onward [11]. These are mainly pharmaceutical compounds, but also include food additives, industrial chemicals and agrochemicals [28]. The latest version at the time of writing, 2011.2, contains 62,465 molecules and 103,907 biotransformation reactions, of which 36,041 are in humans.…”