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Bioorg Med Chem. 2015 Feb 15;23(4):770-8. doi: 10.1016/j.bmc.2014.12.063. Epub 2015 Jan 3.

Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.

Author information

1
Dart NeuroScience, LLC, San Diego, CA 92131, USA. Electronic address: rrojas@dartneuroscience.com.
2
Departments of Chemistry and Biochemistry, Emory University, Atlanta, GA 30322, USA.
3
Dart NeuroScience, LLC, San Diego, CA 92131, USA.

Abstract

Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.

KEYWORDS:

Biochemical analysis; Enzymatic analysis; Isothermal titration calorimetry; MAO-B; Monoamine oxidase; Small molecule inhibitors; Thermal shift

PMID:
25600407
DOI:
10.1016/j.bmc.2014.12.063
[Indexed for MEDLINE]
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