title: Role of predictive metabolism and toxicity modeling in drug discovery--a summary of some recent advancements.
abstract: In this article, we discuss recent advances and selected publications in the area of computer-based (in silico) metabolism and toxicity prediction, and comment on the opportunities for prediction of metabolism-based toxicity. The article also discusses the growing interest and importance of in silico prediction of metabolism and toxicity as tools to assist in library design and lead optimization. In addition, we consider the status of commercial metabolism and toxicity databases, and the need for future improvement, since data is often from older studies and from structures not typically considered as 'drug-like'. The article highlights the current status and potential of in silico models for property prediction, and the potential for linkage with vivo models to improve the integration of metabolism and toxicity into the drug discovery process and extrapolation to clinical studies. The article underscores that the future development, integration and application of in silico models will require a balance of local and global model approaches. The article also indicates that implementation and integration of models into drug discovery processes needs to be carried out in a rational and systematic manner, if we are to fully capitalize on the opportunity presented by in silico predictive modeling.
authors.affiliation: Pharmacia Company, 800 N Lindbergh Boulevard, St Louis, MO 63167, USA. alan.g.e.wilson@pharmacia.com
authors.forename: Alan G E
authors.initials: AG
authors.lastname: Wilson
authors.forename: Anita C
authors.initials: AC
authors.lastname: White
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mueller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D027682:Cation Transport Proteins; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004268:DNA-Binding Proteins; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004702:Endocrine Glands / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010600:Pharmacology / Q000379:methods*; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D011237:Predictive Value of Tests; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012984:Software; D014116:Toxicology / Q000379:methods*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D004364:Pharmaceutical Preparations; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D003577:Cytochrome P-450 Enzyme System