The human adenosine A_1tn2_1tnB receptor [Elektronische Ressource] : homology modeling, virtual screening, and computer-aided drug design / vorgelegt von Farag Farouk Sherbiny Selim

Farag Farouk Sherbiny Selim

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• Gesundheit

Informations

• Publié par: rheinische_friedrich-wilhelms-universitat_bonn
• Publié le: 01 janvier 2011
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 6 Mo

Extrait

The Human Adenosine A Receptor: 2B
Homology Modeling, Virtual Screening, and
Computer-aided Drug Design


DISSERTATION
zur
Erlangung des Doktorgrades (Dr. rer. nat.)
der
Mathematisch-Naturwissenschaftlichen Fakultät
der
Rheinischen Friedrich-Wilhelms-Universität Bonn



vorgelegt von

Farag Farouk Sherbiny Selim


aus
Giza, Ägypten


Bonn, 2011


Angefertigt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät
der Rheinischen Friedrich-Wilhelms-Universität Bonn













Promotionskommission

1. Gutachter: Prof. Dr. Christa E. Müller
2. Gutachter: Prof. Dr. Michael Gütschow
3. Fachnahes Mitglied: Prof. Dr. Harald G. Schweim
4. Fachangrenzendes Mitglied: Prof. Dr. Ivar von Kügelgen

Tag der Promotion: 31. Januar 2011
Erscheinungsjahr: 2011
ACKNOWLEDGEMENTS
There are two persons that have been corner stones for the development of this thesis: Prof.
Dr. Christa E. Müller and Dr. Astrid Maaß. I would like to dedicate my thanks to my
supervisor Prof. Dr. Christa E. Müller for offering me the opportunity to do my PhD in her
group at University of Bonn, Germany and for the ideas behind this thesis and for her
guidance throughout this thesis and also for many fruitful discussions while pursuing these
ideas.

I would also like to express my deepest gratitude to Dr. Astrid Maaß not only for her valuable
guidance, technical support and helpful suggestions during the entire work but also for the
wonderful experience. She was very patient and helped me a lot to achieve many experiences
at the beginning of my thesis.

Special thanks also go to the Department of Simulation Engineering at the Fraunhofer
Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany, for
providing me the opportunity to write my PhD thesis and then for financial support for
conferences, particularly our leader group at Fraunhofer Institute, Dr. Dirk Reith. I am also
thankful to my other colleagues in our group, particularly Dr. Karl N. Kirschner and Dr.
Thomas Brandes for their cooperation during my work. I want to thank everybody that shared
office at Fraunhofer Institute during these years, Dr. Thorsten Koeddermann, and Marco
Hulsmann not only for their cooperation, but also for the good atmosphere.

Funding for my PhD research has been provided by the Ministry of Higher Education, Egypt

Farag Selim















DEDICATION

To the memory of my father

To my beloved mother, my wife and my children’s

 


CONTENTS I
CONTENTS
1 INTRODUCTION ………………………………………………………………….. 1
1.1 G Protein-Coupled Receptors ………………………………………………… 1
1.2 Adenosine Receptors ………………………………………………………….. 3
1.3 Adenosine A Receptor ……………………………………………………… 52B
1.4 Therapeutic Applications of the A Receptor Ligands ………………………. 82B
1.5 Adenosine A Receptor Agonists ……………………………………………. 92B
1.6 Adenosine A Receptor Antagonists ………………………………………… 112B
1.6.1 Xanthine Antagonists ................................................................................ 11
1.6.2 9-Deazaxanthines ...................................................................................... 14
1.6.3 Non-xanthine Antagonists ......................................................................... 15
1.6.4 Triazolotriazine Antagonists ..................................................................... 17
1.7 Progress on A Receptor Research …………………………………………... 172B
1.8 Aim of the Present thesis …………………………………………………….. 18
2 GENERATION OF 3D-STRUCTURE MODELS ……………………………… 21
2.1 Introduction …………………………………………………………………… 21
2.2 Homology Modeling ………………………………………………………….. 22
2.2.1 GPCR Template Structures ……………………………………………... 22
2.2.2 Sequence Alignment ……………………………………………………. 27
2.2.3 3D Structure Creation …………………………………………………... 31
2.2.4 Adding Amino Acid Side-chains ……………………………………...... 31
2.2.5 System Setup ……………………………………………………………. 31
2.2.6 Energy Minimization and MD Simulations …………………………….. 32
2.2.6.1 Molecular Mechanics …………………………………………… 32II CONTENTS
2.2.6.2 Force Fields ……………………………………………………... 32
2.2.6.3 Energy Minimization ………………………………………….... 33
2.2.6.4 MD Simulations ………………………………………………… 34
2.2.7 Model Evaluation ……………………………………………………….. 34
2.2.8 Docking Studies ………………………………………………………… 35
2.2.8.1 FlexX Docking ………………………………………………….. 35
2.2.8.2 Affinity Prediction …………………………………………….... 37
2.3 Results and Discussion ………………………………………………………... 38
2.3.1 Homology Modeling …………………………………………………… 38
2.3.2 Template Description …………………………………………………… 40
2.3.3 Evaluation of the Predicted Models …………………………….............. 42
2.3.4 Docking Study Results ………………………………………………….. 47
2.3.5 Docking of ligands into the adenosine A receptor …………................. 502A
2.3.6 Probing of the adenosine A models by docking of selected antagonists 2B
(theophylline, ZM241385, MRS1706, and PSB-601) and selection of the
most suitable model for further studies ………………………………….. 66
2.3.7 Docking of a larger set of compounds to A -III ………………….......... 712B
2.4 Conclusions …………………………………………………………………… 87
3 CONFORMATIONAL CHANGES INDUCED BY AGONIST ………………. 89
3.1 Introduction …………………………………………………………………… 89
3.2 Material and Methods ………………………………………………………… 97
3.2.1 Model Construction ……………………………………........................... 97
3.2.2 Docking of A Receptor Agonist and Antagonist ……………............... 972B
3.2.3 Molecular Systems ……………………………….................................... 99
3.2.4 Molecular Dynamic Simulations ……………………………….............. 100CONTENTS III
Results and Discussion ……………………………………………………................. 101
3.4 Conclusions ……………………........................................................................ 113
4 VIRTUAL (IN SILICO) SCREENING OF THE ADENOSINE A 2B
RECEPTOR …………………………………………………………………….. 115
4.1 Introduction …………………………………………………………………… 115
4.2 Material and Methods ………………………………………………………… 120
4.2.1 Homology Model Preparation …………………………………….......... 120
4.2.2 Database Preparation ……………………………………….................... 121
4.2.3 Docking Procedure ………………………………………………........... 122
4.2.4 Scoring Function ………………………………………………….......... 122
4.2.4.1 FlexX score …………………………………………………….... 123
4.2.4.2 Interaction Fingerprints ………………………………………….. 123
4.2.4.3 Rescoring by MM-GBSA ……………………………………….. 124
4.3 Results and Discussion ………………………………………………………... 125
4.3.1 FlexX-program Database Virtual Screening ……………………............ 126
4.3.2 Rescoring by MM-GBSA ……………………………………................ 127
4.4 Conclusion ……………………………………………………………………. 167
5 SUMMARY AND OUTLOOK ………………………………………………....... 169
6 REFERENCES …………………………………………………………………..... 173