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

Abstract

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

Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases

“…Among the proposed targets, wascholesteryl ester transfer protein (CETP), a target involved in lipoprotein metabolism, was shown to be activated by leoligin in subsequent experimental testing. On the other side, leoligin was also predicted to inhibit the cytochrome P450 (CYP) isoforms 1A2, 2C9, and 3A4 [150], which are involved in the metabolic clearance of exogenous compounds. While it was not active on CYP1A2, it was a weak inhibitor on CYP2C9, and a sub-micromolar IC 50 was determined for CYP3A4 [150].…”

“…On the other side, leoligin was also predicted to inhibit the cytochrome P450 (CYP) isoforms 1A2, 2C9, and 3A4 [150], which are involved in the metabolic clearance of exogenous compounds. While it was not active on CYP1A2, it was a weak inhibitor on CYP2C9, and a sub-micromolar IC 50 was determined for CYP3A4 [150]. Inhibition of CYP enzymes can cause severe drug-drug interactions that may lead to serious adverse effects and eventually require the termination of a drug development project.…”

Virtual screening applications in short-chain dehydrogenase/reductase research

“…Different computational programs can generate different VS results even when the same chemical library and protein structural information are used, and each approach by its own yields valuable results [202, 203]. Thus, combining different computational programs may be crucial for substrate identification or toxicological approaches, where a more complete recovery of the active compounds is needed [204]. Another drawback in the VS process, especially for substrate identification purposes, represents the fact that the available chemical databases are not fully representative.…”

Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

“…Additionally, potential drug–drug interactions via the cytochrome P450 enzyme system were predicted. Compound 7 was experimentally shown to be a potent CYP3A4 inhibitor, while CYP1A2 and CYP2C9 were only weakly inhibited [ 31 ].…”