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Computational Study of Therapeutic and ADME Associated Proteins View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ScholarBank@NUS COMPUTATIONAL STUDY OF THERAPEUTIC TARGETS AND ADME-ASSOCIATED PROTEINS AND APPLICATION IN DRUG DESIGN ZHENG CHANJUAN (M.Sc. ChongQing Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2006 Computational study of therapeutic targets and ADME-associated proteins and application in drug design Acknowledgements ACKNOWLEDGEMENTS This thesis would not have been possible to be completed without the kind support, help, and guidance by lots of people. First of all, I would like to express my deep gratitude to my thesis advisor Dr. Chen Yuzong. He provides me with the guidance, support, and encouragement during my years at National University of Singapore. His advice and insights guided me throughout my doctoral studies. Likewise, his professional knowledge and kind patience kept me motivated to complete my Ph.D. thesis. His commentary and counsel I retain in my mind will continue to guide me through my professional career in future. Also, I would like to thank my current colleagues and friends for their support and collaboration in my academic research and daily life: Mr. Yap Chun Wei, Mr. Han Lianyi, Mr. Lin Honghuang, Mr. Zhou Hao, Mr. Xie Bin, Ms. Cui Juan, Ms. Zhang Hailei, Ms. Tang Zhiqun, Ms. Jiang Li, Mr. Li Hu, Mr. Ung Choong Yong. We shared lots of precious experience and happy life in Singapore, which are the treasures in my life. Although my doctoral study has come to an end, the friendship between us will remain. In addition, I would also like to thank my former colleagues for their helpful discussion, advice, guidance and encouragement on my studies and research: Dr. Cao Zhiwei, Dr. Ji Zhiliang, Dr. Chen Xin, Mr. Wang Jifeng, Ms. Sun Lizhi, Ms. Yao Lixia, and Dr. Xue Ying. I would also like to give special thanks to my husband and my parents for their endless love, support, and encouragement. I dedicate this thesis to them with all my love. - I - Computational study of therapeutic targets and ADME-associated proteins and application in drug design Table of Countents TABLE OF CONTENTS ACKNOWLEDGEMENTS........................................................................................... I TABLE OF CONTENTS.............................................................................................. II SUMMARY .................................................................................................................IV LIST OF TABLES ..................................................................................................... VII LIST OF FIGURES ..................................................................................................VIII ACRONYMS...............................................................................................................IX 1 Introduction...........................................................................................................10 1.1 Overview of target discovery in pharmaceutical research.......................10 1.1.1 Process of drug discovery ................................................................10 1.1.2 Brief introduction to target discovery..............................................11 1.2 Overview of bioinformatics and its role in facilitating drug discovery...13 1.2.1 Brief introduction to bioinformatics ................................................14 1.2.2 Brief introduction to bioinformatics databases................................18 1.3 The need for computational study of therapeutic targets and ADME-associated proteins ...................................................................................21 1.3.1 The need for development of pharmainformatics databases............21 1.3.2 In silico mining of therapeutic targets .............................................26 1.4 Objective and scope of the thesis.............................................................27 1.5 Layout of the thesis..................................................................................29 2 Methodology.........................................................................................................31 2.1 Strategy of pharmainformatics database development ............................31 2.1.1 Preliminary plan of the pharmainformatics database.......................31 2.1.2 Collection of pharmainformatics database information...................32 2.1.3 Organization and structure of pharmainformatics database.............33 2.2 Computational methods for the prediction of druggable proteins ...........39 2.2.1 Introduction to machine learning.....................................................39 2.2.2 Introduction to support vector machines..........................................41 2.2.3 The theory and algorithms of support vector machines...................42 2.2.4 Model evaluation of support vector machines.................................45 3 Therapeutic target database and therapeutically relevant multiple-pathways database development ..................................................................................................47 3.1 Therapeutic target database development................................................47 3.1.1 Preliminary plan of therapeutic target database...............................47 3.1.2 Collection of therapeutic target information....................................48 3.1.3 Construction of therapeutic target database.....................................49 3.1.4 Therapeutic target database structure and access.............................50 3.1.5 Statistics of therapeutic targets database data..................................55 3.2 Therapeutically relevant multiple-pathways database development .......57 3.2.1 Preliminary plan of therapeutically relevant multiple-pathways database ..........................................................................................................57 3.2.2 Collection of therapeutically relevant pathway information ...........58 3.2.3 Construction of therapeutically relevant multiple- pathways database ..........................................................................................................60 3.2.4 Therapeutically relevant multiple-pathways database structure and access ..........................................................................................................61 3.2.5 Statistics of therapeutically relevant multiple-pathways database data ..........................................................................................................67 - II - Computational study of therapeutic targets and ADME-associated proteins and application in drug design Table of Countents 4 Computational analysis of therapeutic targets ......................................................69 4.1 Distribution of therapeutic targets with respective disease classes .........70 4.1.1 Distribution pattern of successful target ..........................................70 4.1.2 Targets for the treatment of diseases in multiple classes .................73 4.1.3 Distribution pattern of research targets............................................75 4.1.4 General distribution pattern of therapeutic targets...........................76 4.2 Current trends of exploration of therapeutic targets ................................79 4.2.1 Targets of investigational agents in the US patents approved in 2000-2004 ......................................................................................................79 4.2.2 Known targets of the FDA approved drugs in 2000-2004...............86 4.2.3 Progress and difficulties of target exploration .................................98 4.2.4 Targets of subtype specific drugs...................................................100 4.3 Characteristics of therapeutic targets .....................................................101 4.3.1 What constitutes a therapeutic target? ...........................................101 4.3.2 Protein families represented by therapeutic targets .......................103 4.3.3 Structural folds...............................................................................105 4.3.4 Biochemical classes.......................................................................108 4.3.5 Human proteins similar to therapeutic targets ...............................114 4.3.6 Associated pathways......................................................................116 4.3.7 Tissue distribution..........................................................................117 4.3.8 Chromosome locations...................................................................118 5 Computer prediction of druggable proteins as a step for facilitating therapeutic targets discovery ........................................................................................................121 5.1 Druggable proteins and therapeutic targets............................................122 5.2 Prediction of druggable proteins from their sequence ...........................124 5.2.1 “Rules” for guiding the search of druggable proteins....................126 5.2.2 Prediction of druggable proteins by a statistical learning method.132 6 Computational analysis of drug ADME- associated proteins.............................137 6.1 ADME-associated proteins database .....................................................138 6.2 ADME-associated proteins database as a resource for facilitating pharmacogenetics research .................................................................................141
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