In silico methods for predicting drug-drug interactions with cytochrome P-450s, transporters and beyond

Abstract

Drug-drug interactions (DDIs) are associated with severe adverse effects that may lead to the patient requiring alternative therapeutics and could ultimately lead to drug withdrawal from the market if they are severe. To prevent the occurrence of DDI in the clinic, experimental systems to evaluate drug interaction have been integrated into the various stages of the drug discovery and development process. A large body of knowledge about DDI has also accumulated through these studies and pharmacovigillence systems. Much of this work to date has focused on the drug metabolizing enzymes such as cytochrome P-450s as well as drug transporters, ion channels and occasionally other proteins. This combined knowledge provides a foundation for a hypothesis-driven in silico approach, using either cheminformatics or physiologically based pharmacokinetics (PK) modeling methods to assess DDI potential. Here we review recent advances in these approaches with emphasis on hypothesis-driven mechanistic models for important protein targets involved in PK-based DDI. Recent efforts with other informatics approaches to detect DDI are highlighted. Besides DDI, we also briefly introduce drug interactions with other substances, such as Traditional Chinese Medicines to illustrate how in silico modeling can be useful in this domain. We also summarize valuable data sources and web-based tools that are available for DDI prediction. We finally explore the challenges we see faced by in silico approaches for predicting DDI and propose future directions to make these computational models more reliable, accurate, and publically accessible.

Keywords: Cheminformatics; Computational; Docking; Machine learning; Modeling; Pharmacophore; Physiologically based pharmacokinetics.