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Discovery of Novel Small Α-Amylase Inhibitors Using Structure-Based

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Discovery of Novel Small Α-Amylase Inhibitors Using Structure-Based Controlling Hyperglycemia: Discovery of Novel Small α-Amylase Inhibitors Using Structure-Based Virtual Screening Dissertation zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften (Dr. rer. nat.) eingereicht im Fachbereich Biologie, Chemie, Pharmazie der Freien Universität Berlin vorgelegt von Jamil Al-Asri aus Sana’a, Jemen 2014 Die vorliegende Arbeit wurde von März 2011 bis August 2014 unter der Leitung von Prof. Dr. Gerhard Wolber am Institut für Pharmazie der Freien Universität Berlin angefertigt. 1. Gutachter: Prof. Dr. Gerhard Wolber 2. Gutachter: Prof. Dr. Matthias F. Melzig Disputation am 24. November 2014 Dedication To my parents who keep unconditional supplication (Dua) for me. They did not only raise and nurture me but also taxed themselves dearly over the years for my education and intellectual development. To my wife and my children (Amjd, Molhm, and Rfeef) who have been a constant source of motivation, support, and encouragement during the challenges of postgraduate studies and life. To my brothers (Mahmoud, Yahya, and Ghailaan) who supported me in different aspects during my postgraduate studies. Acknowledgements I would like to express my deep gratitude to Prof. Dr. Gerhard Wolber, my research supervisor, for giving me a chance to pursue my PhD in his computer-aided drug design Lab in the Pharmaceutical and Medicinal Chemistry Department at the Institute of Pharmacy, Freie Universität Berlin. His guidance, encouragement and critiques of this research work were valuable and appreciated. I am particularly grateful for biological testing carried out by research partner Dr. Gyöngyi Gyémánt from the University of Debrecen, Hungary. Many thanks for her valuable collaboration. I would also like to thank Prof. Dr. Matthias F. Melzig for allowing me to perform a part of my biological experiments in the Pharmaceutical Biology Department, Freie Universität Berlin. Assistance provided by Mrs. Cornelia Görick during my work for biological experiments was greatly appreciated. I would like to acknowledge my special thanks to Dr. Jérémie Mortier for his valuable and constructive suggestions and corrections on my thesis. His willingness to give me his time so kindly has been very much appreciated. I would like to express my sincere thanks to Dr. Andrej Perdih, a former member of our group for his valuable advice and generously granting us some commercial compounds that positively contribute in this research. I would like to thank all my colleagues in the computational Lab for their help and grateful assistance. I am particularly thankful for the European program Erasmus Mundus for awarding me a doctoral scholarship for a period of 34 months. Table of Contents Abstract ................................. ......................................................................................viii Zusammenfassung ........................ ....................................................................................... ix 1 Introduction .............................. ........................................................................................ 1 1.1 Classification of α-amylases ..................................................................................... 1 1.2 Enzyme structure and activation mechanism ........................................................... 3 1.3 Diseases related to amylase and its applications ..................................................... 7 1.3.1 Dental caries .................................................................................................... 8 1.3.2 Obesity and type II diabetes ............................................................................. 8 1.3.3 Industrial applications ....................................................................................... 9 1.4 α-Amylase inhibitors ................................................................................................. 9 1.4.1 Peptide-based α-amylase inhibitors ................................................................10 1.4.2 Carbohydrate-based α-amylase inhibitors .......................................................10 1.4.3 Polyphenols ....................................................................................................13 1.4.4 2-aminobenzothiazole .....................................................................................14 1.4.5 Terpenoids ......................................................................................................15 2 Objectives................................ ...................................................................................... 17 3 Methods ................................. ...................................................................................... 19 3.1 Molecular modeling and virtual screening in drug discovery ................................... 19 3.1.1 Pharmacophore modeling ...............................................................................21 3.1.2 Molecular docking ...........................................................................................22 3.1.3 Similarity search and clustering .......................................................................23 3.1.4 Shape-based virtual screening ........................................................................24 3.1.5 Statistical validation of model predictivity.........................................................25 3.2 Biochemical assay ................................................................................................. 27 4 Results ................................. ...................................................................................... 29 4.1 Structural analysis of different α-amylase isoforms and binding sites ..................... 29 4.1.1 Structural investigation of α-amylase ...............................................................30 4.2 Docking using α-amylase inhibitors with previously unknown binding mode ........... 33 4.2.1 Cyanidin derivatives ........................................................................................33 4.2.2 Steviol compounds ..........................................................................................36 4.2.3 Verbascoside ..................................................................................................39 4.3 Structure-Based virtual screening for α-amylase inhibitors ..................................... 43 4.3.1 Pharmacophore-based virtual screening: Initial screening round .....................43 v 4.3.1.1 Development of 3D pharmacophore models ............................................43 4.3.1.2 Virtual screening metrics for the developed pharmacophore model..........47 4.3.1.3 Overall compound selection work-flow .....................................................48 4.3.2 Biological Testing ............................................................................................50 4.3.3 Attempt to rationalize differences in IC50 values ..............................................53 4.3.4 Docking studies with discovered α-amylase inhibitors .....................................56 4.3.5 Similarity search for the best competitive inhibitor in the initial screening ........62 4.3.6 Biological assay and SAR for analogues of the best competitive inhibitor .......62 4.3.7 Docking studies of analogues of the best novel competitive inhibitor ...............66 4.3.8 Refined pharmacophore-based virtual screening ............................................68 4.3.8.1 Development of 3D pharmacophores .......................................................68 4.3.8.2 Protocol of the refined virtual screening ...................................................74 4.3.9 Biological testing of hits selected by the refined virtual screening ....................76 4.3.10 Docking of novel inhibitors identified by the refined virtual screening ..............78 5 Discussion ............................... ...................................................................................... 86 5.1 Natural α-amylase inhibitors with unknown binding mode ...................................... 87 5.2 Virtual screening .................................................................................................... 88 5.2.1 Initial virtual screening .....................................................................................88 5.2.2 Refined virtual screening .................................................................................90 5.2.3 Evaluation of the performed virtual screening approaches ..............................90 6 Conclusion and Prospective .... ...................................................................................... 96 7 Experimental part .................... ...................................................................................... 98 7.1 Binding mode elucidation for inhibitors identified by collaboration partners ............ 98 7.2 Structure-based virtual screening ........................................................................... 98 7.2.1 Commercial chemical databases .....................................................................98 7.2.2 Validation of developed pharmacophores........................................................99 7.2.3 Target preparation for pharmacophore creation ............................................ 101 7.2.4 Pharmacophore creation and virtual screening.............................................. 101 7.3 Biological testing .................................................................................................
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