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Reversible and Irreversible Small Molecule Inhibitors of Monoamine Oxidase B (MAO-B) Investigated by Biophysical Techniques ⇑ Rafael J

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Reversible and Irreversible Small Molecule Inhibitors of Monoamine Oxidase B (MAO-B) Investigated by Biophysical Techniques ⇑ Rafael J Bioorganic & Medicinal Chemistry 23 (2015) 770–778 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques ⇑ Rafael J. Rojas a, , Dale E. Edmondson b, Terri Almos a, Roderick Scott a, Mark E. Massari a a Dart NeuroScience, LLC, San Diego, CA 92131, USA b Departments of Chemistry and Biochemistry, Emory University, Atlanta, GA 30322, USA article info abstract Article history: Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter crit- Received 16 September 2014 ical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target Revised 15 December 2014 for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson’s dis- Accepted 24 December 2014 ease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift Available online 3 January 2015 and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermody- namically privileged chemical scaffolds. Described here is the development of such approaches for Keywords: reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant Monoamine oxidase MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles MAO-B Isothermal titration calorimetry of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpical- Thermal shift ly favorable and entropically unfavorable binding, in contrast to reversible compounds, which were char- Biochemical analysis acterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The Enzymatic analysis biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B Small molecule inhibitors inhibitors. Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction (L-3,4-dihydroxyphenylalanine) resulted in improved episodic memory formation6 and MAO-B inhibitors have been shown to The central role of dopaminergic signaling in memory and cog- improve memory in rodent models7–9 as well as Alzheimer’s dis- nition is well established.1 Reduced dopaminergic neurotransmis- ease (AD) patients.10,11 In addition to its well established role in sion can contribute to cognitive decline in disorders such as monoamine degradation, MAO-B was recently shown to play an Parkinson’s disease (PD).2 Inhibition of the key metabolic enzyme important role in c-aminobutyric acid (GABA)-mediated synaptic for dopamine, monoamine oxidase B (MAO-B), is a clinically vali- inhibition by reactive astrocytes in mouse models of AD.12,13 For dated approach for maintaining dopaminergic signaling in PD these reasons, there has been a reemergence of drug discovery patients and can improve cognitive function in addition to the clas- efforts targeting MAO-B for AD and other disorders of memory sical motor symptoms.3 During aging, dopamine levels decrease, and cognition.14 while MAO-B expression increases 3-fold.4 In addition to mono- Monoamine oxidases are flavin-dependent enzymes responsi- amine degradation, MAO-B activity results in the generation of ble for the oxidative deamination of monoamine neurotransmit- hydrogen peroxide which can promote oxidative stress and mito- ters. The two MAO isoenzymes, MAO-A and MAO-B, share 70% chondrial dysfunction during aging.5 These findings suggest that sequence identity and metabolize serotonin and dopamine, respec- therapeutic maintenance of dopamine may be a strategy to improve tively. Both enzymes are monotopically inserted into the outer cognitive function in the elderly. In support of this concept, mitochondrial membrane by a single C-terminal hydrophobic treatment of otherwise healthy elderly patients with L-DOPA helix. Although MAO-B forms homodimeric structures, there is no evidence of cross-talk between the two active sites.15 Currently, the only FDA-approved MAO-B-selective inhibitors, selegiline Abbreviations: AD, Alzheimer’s disease; ANS, 1-8-anilinonaphthalene sulfonate; (L-deprenyl,) and rasagiline (Azilect), are irreversible, forming FAD, flavin adenine dinucleotide; ITC, isothermal titration calorimetry; MAO, covalent adducts to the flavin adenine dinucleotide (FAD) cofactor monoamine oxidase; PBS, phosphate-buffered saline; PD, Parkinson’s disease; RFU, 16–18 relative fluorescence units; RLU, relative luminescence units. within the MAO-B active site. More recently, there has been an ⇑ Corresponding author. Tel.: +1 858 246 8151. effort to develop reversible MAO-B inhibitors with higher selectiv- E-mail address: [email protected] (R.J. Rojas). ity for MAO-B over MAO-A in order to circumvent off-target http://dx.doi.org/10.1016/j.bmc.2014.12.063 0968-0896/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). R.J. Rojas et al. / Bioorg. Med. Chem. 23 (2015) 770–778 771 liabilities, such as hypertensive crisis associated with inhibition of MAO-A in the gastrointestinal tract.19 This has resulted in next- generation reversible MAO-B inhibitors, such as lazabemide (Roche), EVT-302 (Evotec), safinamide (Newron Pharmaceuticals), and HT-3951 (Dart NeuroScience) entering clinical trials. Described here is the development of biophysical approaches using isother- mal titration calorimetry (ITC) and thermal shift which can compli- ment traditional measures of affinity and enable the discovery of next-generation MAO-B inhibitors. ITC allows for the complete thermodynamic characterization of inhibitor binding by measuring the heat evolved upon complex formation. The change in free energy (DG) upon inhibitor binding can be defined by changes in both enthalpy (DH) and entropy 20 (DS) and is directly related to binding affinity (KD). Favorable enthalpic contributions are largely driven by specific bonding net- works mediated by hydrogen bonds, shape complementarity (van der Waals’ interactions), and salt bridges, while favorable entropic contributions are derived from bulk hydration effects, such as the release of water molecules upon binding, hydrophobic interac- tions, or an increase in the conformational flexibility of the protein or ligand.20 Retrospective studies have shown that best-in-class Figure 1. Structures of MAO-B inhibitors. drugs demonstrate improved enthalpy values relative to their first-in-class counterparts, supporting the concept that aminopropylether analog of a methyl ester luciferin precursor sub- enthalpically-driven compounds are preferred candidates for drug strate that is then converted into light by the addition of a lucifer- 31 development.21 As such, there is growing support for the notion ase-containing detection solution. The Amplex Red assay is a that thermodynamic studies should be harnessed early in drug dis- fluorescence-based method for measuring hydrogen peroxide for- covery to differentiate chemical scaffolds based on their enthalpic mation, which is a product of substrate oxidation. Hydrogen perox- efficiency.22,23 ide produced by MAO activity is then used by horseradish The capacity for a compound to influence the structural integ- peroxidase to convert non-fluorescent Amplex Red to the fluores- 32,33 rity of a protein can be assessed using plate-based assays for ther- cent product Resorufin. An advantage of the MAO-Glo assay is mal stability.24 Protein thermal stability can be measured using its large signal window and adaptability to screening in high-den- hydrophobic-sensitive fluorophores to monitor protein unfolding sity microtiter plates. However, the reliance on endpoint reading resulting from an increase in temperature using a standard quanti- with a non-native substrate limits its use for detailed biochemical tative PCR instrument. Inhibitor binding results in a shift in the studies. The Amplex Red assay has the advantage of using native substrates with real-time monitoring. observed melting temperature (Tm) providing additional insight into binding modality.25 Fluorescence-based assays for thermal Substrate saturation experiments frequently result in reaction stability are commonly referred to in the literature as thermal shift rates that exceed the assay linear range, this can be overlooked assay (TSA), differential scanning fluorimetry (DSF), temperature- when reading in endpoint mode. Therefore, the MAO-Glo substrate dependent fluorescence (TdF), ThermoFluor, or protein thermal saturation experiments were conducted at multiple time points to shift (PTS). Such assays are increasingly used to characterize and ensure progress curve linearity to 60 min for each substrate con- differentiate compounds during drug discovery.26 centration. Observed Km values for the MAO-Glo substrate were Integral membrane proteins can pose significant challenges to 1.1 (±0.07) lM for soluble and 0.6 (±0.09) lM for microsomal the development of thermal shift and ITC assays27 and although MAO-B (Fig. 2A). These Km values were more potent relative to MAO-B is classified as an integral membrane protein, it can be the published value of 4 lM using microsomal MAO-B, an observa- purified in a soluble form which was crucial to enabling the bio- tion that is most likely the
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