title: RS-predictor: a new tool for predicting sites of cytochrome P450-mediated metabolism applied to CYP 3A4.
abstract: This article describes RegioSelectivity-Predictor (RS-Predictor), a new in silico method for generating predictive models of P450-mediated metabolism for drug-like compounds. Within this method, potential sites of metabolism (SOMs) are represented as "metabolophores": A concept that describes the hierarchical combination of topological and quantum chemical descriptors needed to represent the reactivity of potential metabolic reaction sites. RS-Predictor modeling involves the use of metabolophore descriptors together with multiple-instance ranking (MIRank) to generate an optimized descriptor weight vector that encodes regioselectivity trends across all cases in a training set. The resulting pathway-independent (O-dealkylation vs N-oxidation vs Csp(3) hydroxylation, etc.), isozyme-specific regioselectivity model may be used to predict potential metabolic liabilities. In the present work, cross-validated RS-Predictor models were generated for a set of 394 substrates of CYP 3A4 as a proof-of-principle for the method. Rank aggregation was then employed to merge independently generated predictions for each substrate into a single consensus prediction. The resulting consensus RS-Predictor models were shown to reliably identify at least one observed site of metabolism in the top two rank-positions on 78% of the substrates. Comparisons between RS-Predictor and previously described regioselectivity prediction methods reveal new insights into how in silico metabolite prediction methods should be compared.
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
authors.forename: Jed
authors.initials: J
authors.lastname: Zaretzki
authors.forename: Charles
authors.initials: C
authors.lastname: Bergeron
authors.forename: Patrik
authors.initials: P
authors.lastname: Rydberg
authors.forename: Tao-wei
authors.initials: TW
authors.lastname: Huang
authors.forename: Kristin P
authors.initials: KP
authors.lastname: Bennett
authors.forename: Curt M
authors.initials: CM
authors.lastname: Breneman
mesh_terms: D000082:Acetaminophen / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000082:Acetaminophen; D014859:Warfarin; D051544:Cytochrome P-450 CYP3A