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Cytochrome P450 3A4 (CYP3A4) is the most versatile enzyme involved in drug metabolism. The time-dependent inhibition of CYP3A4 by acacetin, apigenin, chrysin, and pinocembrin was experimentally detected, but not entirely elaborated so far. Thus, a two-level QM/MM (Quantum Mechanics/Molecular Mechanics) model is developed to yield insights into the receptor-flavonoid recognition at the molecular scale. Active site residues and the flavonoid are modelled using SCC-DFTB-D (QM level), while the rest of the complex is treated using AMBER force field (MM level). QM/MM binding free energies are well correlated with experimental data, indicating the largest inhibitory effect of chrysin on enzyme activity at a submicromolar concentration. Consequently, quercetin (QUE) and flavopiridol (FLP) are observed as representative examples of structurally different flavonoids. The inhibition parameters for QUE and FLP are evaluated using the well-calibrated QM/MM strategy, thereby aiding to quantitatively conceive the functional behavior of the whole family of flavonoids. A kinetic threshold for further assessment of the drug-drug interactions underlying the time-dependent inhibition of CYP3A4 by flavonoids is explored. Communicated by Ramaswamy H. Sarma

On the inhibition of cytochrome P450 3A4 by structurally diversified flavonoids