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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

Investigating the Molecular Basis for the Selective Inhibition of Aldehyde Dehydrogenase 2 by the Isoflavonoid Daidzin

Author(s): Thayssa Tavares da Silva Cunha, Felipe Rodrigues de Souza, Pedro de Sena Murteira Pinheiro, Carlos Maurício Rabello de Sant’Anna, François Noël, Tanos Celmar Costa França and Carlos Alberto Manssour Fraga*

Volume 19 , Issue 6 , 2020

Page: [437 - 447] Pages: 11

DOI: 10.2174/1871527319999200817153150

Price: $65


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.

Keywords: ALDH-2, molecular dynamics, daidzin, selective inhibition, isoflavonoids, nucleus accumbens.

Graphical Abstract
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