In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance

摘要: The cytochrome P450 (CYP) superfamily represents the major enzyme class responsible for metabolism of exogenous compounds. Investigation clearance pathways is therefore an integral part in early drug development, as any alteration metabolic enzymes may markedly influence toxicological profile and efficacy novel In silico methods are widely applied development to complement experimental approaches. Several different tools available that purpose, however, CYP they have only been retrospectively so far. Within this study, pharmacophore- shape-based models a docking protocol were generated prediction CYP1A2, 2C9, 3A4 inhibition. All theoretically validated models, workflow, additional external bioactivity profiling independently parallel predict inhibition 29 compounds from synthetic natural origin. After subsequent assessment predictions, we analyzed compared prospective performance all methods, thereby defining suitability techniques enzymes. We observed quite substantial differences performances tools, suggesting rational selection virtual screening method proved perform best can largely improve success rates when it comes prediction.