Evaluation of stabilizing additives to protect activities of cytochrome P450 enzymes for in vitro drug testing and pharmacogenetic studies: Focus on CYP2D6.

In vitro and ex vivo studies on drug metabolism and stability are vital for drug development and pre-clinical safety assessment. Traditional in vitro models, such as liver enzyme (S9) fractions and microsomes, often fail to account for individual variability. Personalized models, including 3D cell models and organoids, offer promising alternatives but may not fully replicate physiological processes, especially for Cytochrome P450 (CYP) families involved in extrahepatic metabolism.

Electronic dynamics created at conical intersections and its dephasing in aqueous solution.

A dynamical rearrangement in the electronic structure of a molecule can be driven by different phenomena, including nuclear motion, electronic coherence or electron correlation. Recording such electronic dynamics and identifying its fate in an aqueous solution has remained a challenge. Here, we reveal the electronic dynamics induced by electronic relaxation through conical intersections in both isolated and solvated pyrazine molecules using X-ray spectroscopy.

Generalized Coupled Cluster Theory for Ground and Excited State Intersections.

Coupled cluster theory in the standard formulation is unable to correctly describe conical intersections among states of the same symmetry. This limitation has restricted the practical application of an otherwise highly accurate electronic structure model, particularly in nonadiabatic dynamics. Recently, the intersection problem among the excited states was fully characterized and resolved.

Determining Minimum Energy Conical Intersections by Enveloping the Seam: Exploring Ground and Excited State Intersections in Coupled Cluster Theory.

Minimum energy conical intersections can be used to rationalize photochemical processes. In this Letter, we examine an algorithm to locate these structures that does not require the evaluation of nonadiabatic coupling vectors, showing that it minimizes the energy on hypersurfaces that envelop the intersection seam. By constraining the states to be separated by a small non-zero energy difference, the algorithm ensures that numerical artifacts and convergence problems of coupled cluster theory at conical intersections are not encountered during the optimization.