BACKGROUND: ALDH-2 has been considered an important molecular target for the treatment of drug addiction due to its involvement in the metabolism of the neurotransmitter dopamine: however, the molecular basis for the selective inhibition of ALDH-2 versus ALDH-1 should be better investigated to enable a more pragmatic approach to the design of novel ALDH-2 selective inhibitors. OBJECTIVE: In the present study, we investigated the molecular basis for the selective inhibition of ALDH-2 by the antioxidant isoflavonoid daidzin (IC50 = 0.15 μM) compared to isoform 1 of ALDH through molecular dynamics studies and semiempirical calculations of the enthalpy of interaction. METHODS: The applied methodology consisted of performing the molecular docking of daidzin in the structures of ALDH-1 and ALDH-2 and submitting the lower energy complexes obtained to semiempirical calculations and dynamic molecular simulations. RESULTS: Daidzin in complex with ALDH-2 presented directed and more specific interactions, resulting in stronger bonds in energetic terms and, therefore, in enthalpic gain. Moreover, the hydrophobic subunits of daidzin, in a conformationally more restricted environment (such as the catalytic site of ALDH-2), promote the better organization of the water molecules when immersed in the solvent, also resulting in an entropic gain. CONCLUSION: The molecular basis of selective inhibition of ALDH-2 by isoflavonoids and related compounds could be related to a more favorable equilibrium relationship between enthalpic and entropic features. The results described herein expand the available knowledge regarding the physiopathological and therapeutic mechanisms associated with drug addiction.

Center for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

Department of Fundamental Chemistry Chemistry Institute Federal Rural University of Rio de Janeiro Seropédica RJ Brazil

Graduate Program in Pharmacology and Medicinal Chemistry Institute of Biomedical Sciences Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil

Laboratory of Evaluation and Synthesis of Bioactive Substances Institute of Biomedical Sciences Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil

Laboratory of Molecular Biochemical and Pharmacology Institute of Biomedical Sciences Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ Brazil

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