title: Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
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.
authors.affiliation: Dart NeuroScience, LLC, San Diego, CA 92131, USA. Electronic address: rrojas@dartneuroscience.com.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Rojas
authors.affiliation: Departments of Chemistry and Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson
authors.affiliation: Dart NeuroScience, LLC, San Diego, CA 92131, USA.
authors.forename: Terri
authors.initials: T
authors.lastname: Almos
authors.affiliation: Dart NeuroScience, LLC, San Diego, CA 92131, USA.
authors.forename: Roderick
authors.initials: R
authors.lastname: Scott
authors.affiliation: Dart NeuroScience, LLC, San Diego, CA 92131, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Massari
mesh_terms: D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D008996:Monoamine Oxidase Inhibitors; D054852:Small Molecule Libraries; D008995:Monoamine Oxidase
keywords: Biochemical analysis; Enzymatic analysis; Isothermal titration calorimetry; MAO-B; Monoamine oxidase; Small molecule inhibitors; Thermal shift