Modulation des isoenzymes CYP450 pour prévenir le cancer mammaire induit par le DB[a, l]P
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Les substances cancérigènes se transforment en métabolites électrophiles, se lient à l'ADN et provoquent le cancer par le biais de l'activation métabolique, de la détoxification, de l'angiogenèse et des métastases. Les isozymes CYP sont des cibles thérapeutiques dans le cancer mammaire induit par le DBP. LBVS, l'amarrage moléculaire, les simulations MD et les études in vitro se sont concentrés sur CYP1A1, 1A2 et 1B1. LBVS a identifié des hits, les a affinés en utilisant les filtres RO5 et ADMET de Lipinski et les a amarrés à l'aide d'AutoDock4. CHEMBL1, CHEMBL2 et CHEMBL3 ont montré des affinités de liaison supérieures au FNA. La stabilité a été confirmée par des simulations MD. Le filtrage ADMET a donné des résultats non toxiques, ANA8430692 et ANA7923580 présentant une stabilité optimale. Des essais de dynamique moléculaire et d'inhibition enzymatique ont validé leur potentiel en tant qu'inhibiteurs du CYP. Les analogues conçus ANA6917483, ANA8430692 et ANA6451816 ont présenté des modèles de liaison et d'interaction forts, suggérant un potentiel anticancéreux. Cette étude nous permet de mieux comprendre la prévention du cancer mammaire induite par le DBP.
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