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Identification of Novel Monoamine Oxidase B Inhibitors from Ligand Based Virtual Screening

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Identification of Novel Monoamine Oxidase B Inhibitors from Ligand Based Virtual Screening Identification of novel monoamine oxidase B inhibitors from ligand based virtual screening A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Mohammed Alaasam August, 2014 Thesis written by Mohammed Alaasam B.S., University of Baghdad, 2007 M.S., Kent State University, 2014 Approved by Werner Geldenhuys , Chair, Master’s Thesis Committee Richard Carroll , Member, Master’s Thesis Committee Prabodh Sadana , Member, Master’s Thesis Committee Eric Mintz , Director, School of Biomedical Sciences James Blank , Dean, College of Arts and Sciences ii Table of Contents List of figure ...................................................................................................................... vi List of tables ..................................................................................................................... xiii Acknowledgments............................................................................................................ xiv Chapter one: Introduction ............................................................................................... 1 1.1.Parkinson's disease ....................................................................................................... 1 1.2.Monoamine oxidase enzymes ....................................................................................... 7 1.3.Structures of MAO enzymes ....................................................................................... 12 1.4.Three dimentiona structure of MAO-B enzyme ......................................................... 13 1.4.1. membrane binding domain ............................................................................ 14 1.4.2. FAD binding domain ..................................................................................... 16 1.4.2.1.Role of aromatic cage in MAO-B catalysis ........................................... 22 1.4.3. Substrate binding domain .............................................................................. 27 1.5.Structural comparison between human MAO-B and human MAO-A ....................... 34 1.5.1. Oligomeric state of MAO enzymes ............................................................... 35 1.5.2. Membrane binding domain structural differences ......................................... 36 1.5.3. FAD binding domain structural differences .................................................. 36 1.5.4. Substrate binding domain structural differences ........................................... 36 1.6.Neuroprotective effect of MAO-B inhibitors ............................................................. 39 iii 1.7.Oxidative deamination reaction of MAO enzymes .................................................... 41 1.7.1. Reductive half reaction .................................................................................. 42 1.7.1.1.Proposed mechanisms of Cα—H cleavage ............................................ 44 1.7.1.2.Polar nucleophilic mechanism ............................................................... 47 1.7.2. Oxidative half reaction .................................................................................. 49 1.8.Structural mechanism of MAO inhibtion ................................................................... 49 1.9.LSD1 enzyme .............................................................................................................. 54 1.9.1. Three dimensional structure of LSD1 ........................................................... 56 1.9.2. Substrate specificity of LSD1 enzyme .......................................................... 58 Chapter two: Methods and Materials ........................................................................... 62 2.1.Overview ..................................................................................................................... 62 2.2.Monoamine oxidase inhibition assay .......................................................................... 68 2.3.LSD1 inhibitor screening assay .................................................................................. 71 2.4.Docking studies ........................................................................................................... 73 2.5.Bovine serum albumin binding assay ......................................................................... 73 2.6.Parallel Artificial Membrane Permeability Assay (PAMPA) ..................................... 75 Chapter three: Results .................................................................................................... 78 3.1.MAO inhibition assay results...................................................................................... 78 3.1.1. MAO-B inhibition assay results .................................................................... 84 iv 3.1.2. MAO-A inhibition assay results .................................................................... 84 3.2. MAO-B docking studies results ............................................................................... 90 3.3. LSD1 inhibition assay results ................................................................................ 102 3.4. LSD1 docking studies results................................................................................. 104 3.5. Bovine serum albumin binding assay results ......................................................... 115 3.6. Parallel artificial membrane permeability assay results ......................................... 118 Chapter four: ................................................................................................................. 121 4.1.Discussion................................................................................................................. 121 4.2.Structure activity relationships ................................................................................. 140 Bibliography .................................................................................................................. 147 v List of figures Figure (1): Simple oxidative deamination reaction ............................................................ 9 Figure (2): MAO enzyme specifities for amine substrates. .............................................. 10 Figure 3: 3D structure of MAO-A as monomer and MAO-B as dimer ........................... 13 Figure (4): Three dimensional structure of MAO-B enzyme ........................................... 15 Figure (5): Covalent binding of MAO enzyme to isoalloxazine ring of FAD cofactor ... 16 Figure (6): Two dimesional representation of FAD incorporation in MAO-B enzyme ... 18 Figure (7): Three dimensional demonstration of phenolic side chain of Tyr398 in perpendicular position to flavin ring of MAO-B enzyme. ............................ 20 Figure (8): Covalent flavinylation of MAO-B enzyme .................................................... 21 Figure (9): Three dimensional representation of aromatic cage in MAO-B enzyme crystal structure (top view) ........................................................................................ 22 Figure (10): Proposed nucleophilic mechanism of reductive phase of MAO catalysis .... 23 Figure (11): Three dimensional representation of bent form of reduced flavin ring of MAO-B crystal structure ............................................................................... 24 Figure (12): Simplified demonstration of suggested role of aromatic cage in MAO-B catalysis .......................................................................................................... 25 Figure (13): P-nitrobenzylamine and P-nitrophenethylamine structures .......................... 26 Figure (14): Three dimentional image of MAO-B enzyme crystal to illustrate loop99-112, gating residues, entrance and substrate cavities ............................................ 28 Figure (15): Three dimensional reoresentation of Ile199 and Tyr326 .............................. 29 vi Figure (16): Three dimensional representation of (A) open and (B) close conformation of Ile199 side chain of MAO-B enzyme ............................................................................... 31 Figure (17): Comparison of MAO-A monopartite and MAO-B dipartite active sites cavities ........................................................................................................... 33 Figure (18): Metabolic pathway of dopamine with its precursors and metabolites .......... 40 Figure (19): Metabolic action of MAO-B enzyme on MPTP ........................................... 41 Figure (20): Oxidation-reduction reaction of flavin ring of FAD cofactor ...................... 42 Figure (21):Oxidative deamination reaction mediated by MAO enzymes ....................... 43 Figure (22): Proposed hydride mechanism of Cα—H cleavage reaction of reductive half reaction in flavoenzymes ............................................................................... 44 Figure (23): Proposed heterolytic proton abstraction (single electron transfer) of Cα—H cleavage reaction of reductive half reaction in flavoenzymes ....................... 45 Figure (24): Proposed heterolytic hydrogen abstraction of Cα—H cleavage reaction of reductive half reaction in flavoenzymes ........................................................ 46 Figure (25): Proposed polar nucleophilic mechanism of reductive half reaction in MAO enzymes catalysis ........................................................................................... 48 Figure (26): Rasagiline,
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