Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9.

Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug-drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 µM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 µM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 µM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.

Citrulline stimulates locomotor activity in aged rats: Implication of the dopaminergic pathway.

OBJECTIVES: A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mechanism is unknown. The aim of this study was to determine the effect of CIT administration on locomotor activity and dopamine activity in healthy aged rats. METHODS: Sixty adult (3-mo-old) and aged (20-mo-old) rats were divided into four groups (n = 15 each) stratified by age (adult versus old) and diet (control versus CIT; i.e., Ad-Control, Ad-CIT, Old-Control, Old-CIT) and fed for 4 d on either a CIT-enriched diet (5 g/kg daily; Ad-CIT and Old-CIT) or an isonitrogeneous control diet (Ad-Control and Old-Control). Locomotor activity was evaluated in a Y-maze. On day 5, animals were sacrificed and brain (striatum) was removed to determine total and phosphorylated forms of tyrosine hydroxylase (TH) by immunohistochemistry. RESULTS: CIT restored locomotor activity in aged rats (arm visits: Old-CIT 28 ± 1 versus Old-Control 23 ± 1; P < 0.05), associated with an increase in total TH (Old-CIT 668 ± 27 versus Old-Control 529 ± 22; P < 0.05) and phosphorylated forms of TH (Old-CIT 1012 ± 39 versus Old-Control 589 ± 69; P < 0.05). CONCLUSION: In aged rats, CIT is able to stimulate locomotor activity via the dopaminergic pathway.