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.