Investigation and Modeling of Binding Modes of Novel Small-Molecule Nox2 Inhibitors 公开

Smolar, David Evan (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/mg74qm252?locale=zh
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Abstract


Abstract
Investigation and Modeling of Binding Modes of Novel Small-Molecule
Nox2 Inhibitors
The NADPH Oxidase Nox2 and its homologues are to play a central role in the
production of harmful reactive oxygen species (ROS). Overexpression of ROS is
believed to be involved in the pathophysiology of a number of chronic and acute
disease states affecting millions of people. The binding orientation and site of
novel small-molecule Nox2 inhibitors, believed to bind to the Nox2 subunit
p47phox to inhibit its association with p22phox, was undertaken using GLIDE
docking. A ligand orientation, with a hydrogen bond acceptor oriented towards
the amine of Trp 263, was discovered along with a nearby hydrophobic
occupation in a site previously occupied by proline residues of the PRR of
p22phox. A model of this interaction was created and applied to the virtual
screening of molecular libraries.
By David E. Smolar


Investigation and Modeling of Binding Modes of Novel Small-Molecule
Nox2 Inhibitors


By
David E. Smolar
Bachelor of Science, Emory University 2007
Advisor: Dennis C. Liotta
Advisor: Jim P. Snyder
A thesis submitted to the Faculty of the James T. Laney School of Graduate
Studies of Emory University in partial fulfillment of the requirements for the
degree of Master of Sciences
2010

Table of Contents

Table of Contents

Introduction: ................................................................................................................................... 1
Background: ................................................................................................................................... 3
Unmet Medical Need: Physiological Importance of ROS and NADPH Oxidases ........... 3
Structure of Nox2: ................................................................................................................... 10
Introduction to drug-like properties: ...................................................................................... 15
Current Lead Scaffolds and Known Structure-Activity Relationship (SAR): .................. 19
SAR Rationale for Concerns of Covalent Binding .............................................................. 26
Methodology: ............................................................................................................................... 28
Description of Docking Methodology, Glide Software and Scoring Functions: ............. 28
Glide Docking: ......................................................................................................................... 33
Induced Fit Docking: ............................................................................................................... 34
Virtual Screening of Molecular Libraries: ............................................................................. 35
ROCS Searching: .................................................................................................................... 37
Results and Discussion: ............................................................................................................. 38
Model of Binding Orientation: ................................................................................................ 38
Predictive Studies of AS-99 Derivatives: ............................................................................. 49
Molecular Library Screening: ................................................................................................. 52
ROCS Searching: .................................................................................................................... 55
Conclusion: ............................................................................................................................... 56
References: .................................................................................................................................. 59




List of Figures
Figure 1: Inactive Nox2; courtesy of Susan M. E. Smith of Emory University ................... 12
Figure 2: Activated Nox2; Courtesy of Susan M. E. Smith of Emory University ............... 13
Figure 3: p47phox-p22phox binding showing the protein recognition region of p22phox with
the p47phox dual SH3 domain receptor
..................................................................................... 15
Figure 4: Structure of sulfur scaffold and ebselen ................................................................. 20
Figure 5: Structure of the oxazole containing ligand TG4-225-2. ........................................ 20
Figure 6: Dose response curve for TG4-225-2 ....................................................................... 21
Figure 7: Inactive compounds with substitution at the sulfur position ................................. 21
Figure 8: Compounds with opened thiazole ring .................................................................... 22
Figure 9: Compounds with methylene dioxy, ester or nitro substituents ............................ 22
Figure 10: JM3-77C, 87B & 87C ............................................................................................... 23
Figure 11: FP dose-response curves for JM3- 77C, 87B & 87C ........................................ 23
Figure 12: Structure of AS-99.................................................................................................... 24
Figure 13 : Structures of AS-108 & AS-109 ............................................................................. 24
Figure 14: Nucleophilic opening of the thiazol ring ................................................................ 27
Figure 15: Summary of SAR data relating to susceptibility to nucleophilic attack ............ 27
Figure 16: Representation of favored docking pose (JM3-77C docked in p47phox)........... 39
Figure 17: Top docked pose of JM3-53 in p47phox ................................................................. 40
Figure 18: Second favored pose of JM3-53 in p47phox .......................................................... 40
Figure 19: Docked pose of TG4 225-2 in p47phox ................................................................... 41
Figure 20: TG4-140 docked in p47phox ..................................................................................... 41
Figure 21: JM3-77C docked in p47phox ..................................................................................... 42
Figure 22: JM3-77C docked orientation shown with P22phox ................................................ 43
Figure 23: JM3-87B docked in p47phox ..................................................................................... 44
Figure 24: JM3-87C docked in p47phox ..................................................................................... 45

Figure 25: AS-99 docked in p47phox

.......................................................................................... 45
Figure 26: AS-99 docked orientation shown with p22phox...................................................... 46
Figure 27: AS-109 docked in p47phox ........................................................................................ 46
Figure 28: AS-108 docked in p47phox ........................................................................................ 47
Figure 29: AS-99 scaffold derivatives for predictive studies ................................................. 50
Figure 30: Ethyl substitution at R1 in 1 ..................................................................................... 51
Figure 31: Proline mimetic at R1 in number 4 ......................................................................... 52
Figure 32 : Diels-Alder adduct in number 2 .............................................................................. 52
Figure 33: Representative hits from virtual screening of Chembridge Library .................. 54
Figure 34: Representative hits from ROCS searching .......................................................... 56
















List of Tables
Table 1: IC50 values and docking scores ................................................................................ 48









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