Concepts to interfere with protein-protein complex formations [Elektronische Ressource] : data analysis, structural evidence and strategies for finding small molecule modulators / vorgelegt von Peter Block

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• Publié par: philipps-universitat_marburg
• Publié le: 01 janvier 2005
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 11 Mo

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CONCEPTS TO INTERFERE WITH PROTEIN-PROTEIN
COMPLEX FORMATIONS:
DATA ANALYSIS, STRUCTURAL EVIDENCE AND STRATEGIES
FOR FINDING SMALL MOLECULE MODULATORS
DISSERTATION
ZUR
ERLANGUNG DES DOKTORGRADES
DER NATURWISSENSCHAFTEN
(DR. RER. NAT.)
dem
Fachbereich Pharmazie der
PHILIPPS-UNIVERSITÄT MARBURG
vorgelegt von
Peter Block
aus Bergisch Gladbach
Marburg an der Lahn, im November 2005Vom Fachbereich Pharmazie der PHILIPPS-UNIVERSITÄT MARBURG als Dissertation
angenommen am: 15.12.2005
Erstgutachter: Prof. Dr. G. Klebe
Zweitgutachter: Prof. Dr. E. Hüllermeier
Tag der mündlichen Prüfung: 16.12.2005I would like to express my gratitude to
PROF. DR. GERHARD KLEBE for being a patient supervisor and for supporting this
work with ideas, criticism, and encouragement.
PROF. DR. EYKE HÜLLERMEIER for collaboration in the EPIC project and guidance
in the field of Machine Learning.
DR. CHRISTOPH SOTRIFFER for helpful discussions and hints during the entire PhD
and for the very accurate reviewing of the manuscript. The teamwork in the
development of AFFINDB was outstanding.
JURI PÄRN for the enjoyable collaboration in the EPIC project.
the group of PROF. DR. ALFRED WITTINGHOFER, namely DR. ALEXANDER WOLF,
DR. CHRISTIAN JELICH-OTTMANN and DR. MICHAEL WEYAND for the collaboration
in the 14-3-3 project and their never-ending patience with the in vitro testing of
compounds.
my room mate HANS VELEC for long and helpful discussions about the projects
and the teamwork in the development of visual DrugScore.
CHRISTOF GERLACH and MATTHIAS ZENTGRAF for assistance in various screening
applications and NILS WESKAMP for the help with Cavbase.
DR. ANDREAS BERGNER for support and helpful discussions, especially regarding
the EPIC project.
ANGELA SCHOLZ for invaluable administrative work.
my PARENTS for their love and for their support during my entire PhD.
my girlfriend SARINA for her love, her support, and her never-ending patience.TABLE OF CONTENTS
Introduction ....................................................................................................................... 8
PHYSICOCHEMICAL DESCRIPTORS TO DISCRIMINATE PROTEIN-PROTEIN
INTERACTIONS IN PERMANENT AND TRANSIENT COMPLEXES SELECTED BY
MEANS OF MACHINE LEARNING ALGORITHMS
Introduction ..................................................................................................................... 11
Theory and Methods ....................................................................................................... 18
Protein-Protein Interfaces ........................................................................................... 18
ACE SybylACV with ACE & Sybyl Atom Type Notation (ACV , ACV ) ...................... 20
DrugScore Contact Vectors (DCV) ....................................................................... 21
SFCscore Descriptor Vectors (SDV) ..................................................................... 22
Machine Learning Algorithms ................................................................................... 22
Support Vector Machines (SVM) .......................................................................... 24
Decision Trees (C4.5) ............................................................................................ 25
K Nearest Neighbors (KNN) ................................................................................. 27
Naïve Bayes (NB) .................................................................................................. 27
Feature Selection Approaches .................................................................................... 29
Filter Approach ...................................................................................................... 29
Wrapper Approach ................................................................................................. 30
Genetic Algorithms ................................................................................................ 31
Feature Analysis ......................................................................................................... 32
Results and Discussion ................................................................................................... 33
Classification of Monomer versus Homodimer Complexes ...................................... 33
Classification of Folding Complexes versus Recognition Complexes ...................... 35
Feature Analysis with Genetic Algorithms ................................................................ 39
Summary and Conclusions ............................................................................................. 49
References ....................................................................................................................... 51TABLE OF CONTENTS
STRATEGIES TO SEARCH AND DESIGN STABILIZERS OF PROTEIN-PROTEIN
INTERACTIONS: A FEASIBILITY STUDY
Introduction ..................................................................................................................... 55
Materials and Methods .................................................................................................... 57
Data Analysis and Tools for Virtual Screening .......................................................... 57
Stabilizers of Protein-Protein Interactions ............................................................. 58
Screening for Novel Targets .................................................................................. 58
+The H -ATPase/14-3-3 System .............................................................................. 60
The Fusicoccin Binding Site ................................................................................. 61
Water and the Fusicoccin Binding Pocket ............................................................. 63
Virtual Screening Campaigns ..................................................................................... 65
Preprocessing of the Candidate Molecules ............................................................ 67
Docking Fusicoccin ............................................................................................... 68
“Hot Spot” Analysis .............................................................................................. 69
FTrees .................................................................................................................... 70
Unity Database Search .......................................................................................... 72
Scoring ................................................................................................................... 75
Pharmacophore Post-Filtering ............................................................................... 75
Visual Inspection ................................................................................................... 77
Docking with Gold and AutoDock ........................................................................ 77
Visual DrugScore 78
Results and Discussion 78
+Virtual Screening for Stabilizers of the H -ATPase/14-3-3 Interaction ..................... 86
Summary and Conclusions ........................................................................................... 100
References ..................................................................................................................... 102TABLE OF CONTENTS
AFFINDB: A FREELY ACCESSIBLE DATABASE OF AFFINITIES FOR PROTEIN-
LIGAND COMPLEXES FROM THE PDB
Introduction ....................................................................................................................111
Methods......................................................................................................................... 113
Database Architecture .............................................................................................. 113
Data Collection and Database Content .................................................................... 113
Database Access ...................................................................................................... 118
Discussion ..................................................................................................................... 119
References 123
SUMMARY
Zusammenfassung ......................................................................................................... 127
APPENDIX
Publications Arising from this Work ............................................................................. 132
Articles ..................................................................................................................... 132
Posters ...................................................................................................................... 132
Awards 133
Curriculum Vitae ........................................................................................................... 1348INTRODUCTION
INTRODUCTION
“LIFE IS CONTROLLED BY OVER 50.000 PROTEIN-PROTEIN INTERACTIONS.”
(ANDREW HAMILTON, YALE UNIVERSITY, MARCH 2005, INTERNATIONAL WORKSHOP NAD3 IN RAUISCHHOLZHAUSEN, GERMANY)
Protein-Protein interactions are playing a crucial role in virtually any biological system.
Over the past 10 year great efforts has been made to find molecules, which modulate such
interactions, since the modification of