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Student Number 89541010
Author Wen-Tsai Sung(§º¤å°])
Author's Email Address songchen@ms10.hinet.net
Statistics This thesis had been viewed 3791 times. Download 1441 times.
Department Electrical Engineering
Year 2006
Semester 1
Degree Ph.D.
Type of Document Doctoral Dissertation
Language English
Title Improving Molecular Docking Technology for Computer Aided Drug Design via Energy Minimum Theorem
Date of Defense 2007-01-05
Page Count 224
Keyword
  • Bioinformatics
  • Computer-Aided Drug Design (CADD)
  • Docking
  • Improved Genetic Algorithms
  • Lyapunov Equation Asymptotically stable
  • Minimum Energy
  • WebDeGrator
  • Abstract This investigation presents novel computer graphical and computational schemes for
    solving the challenges of computer-aided drug design (CADD). The application of the
    energy minimum to enhance the docking performance of CADD is discussed in terms
    of three aspects, geometry, energy and activity. American CDC research reports
    reveal that an increasing incurrence of disease, resulting in a requirement to
    accelerate drug discovery. However, commercialization of a new drug is extremely
    complicated. The most significant challenge is the docking procedure in CADD
    according to previous literature. This study applies the energy minimum theorem to
    solve the objection. A geometry search is performed and compared with four types in
    classification of receptors. This work attempts to improve the speed of computer
    simulations of protein folding of protein, and proposes an improved genetic algorithm
    to accelerate the binding site search; second, we focused on energy theme.
    Lyapunov¡¦s stability theorem is adopted to decrease the number of binding sites, thus
    enhancing the docking performance in computer simulation examples. The knot
    insertion and modifying weights of NURBS curves are utilized to accelerate the
    molecular docking system in order to obtain the shortest response route. Finally,
    various drug-ligand interaction models are employed to compute docking simulation,
    and energy minimum theorem is used to judge the approach global energy minimum
    area and docking stability. Various molecular activities are derived at each binding
    site, and the contribution of every bond and non-bond¡¦s in the force field is observed.
    As a benchmark is reference for testing docking performances, the error tolerance of
    computer simulation examples is compared with the X-ray and RMSD experiment
    standard, and the values obtained by Michel, David, Denical and Abraham¡¦s researches performance. This investigation develops the AMBER force field and
    Ullman¡¦s algorithm to support the computer simulation environments. The
    significance of the eigenvalue £f is analyzed at each protein folding, and this study
    performance has increased by 25 percents compared with various binding sites.
    Additionally, the protein folding and various bond forces in drug-ligand interaction
    model are discussed s. Comparing four optimal geometry search methods and referred
    to Pegg and Camila the two been published paper in benchmark of drug docking
    database, the improved genetic algorithms are specified to undertake the search
    binding site and docking, and the global minimum search and the arithmetic
    convergence time of 1.16hr is achieved. Analytical results indicate that the improved
    genetic algorithm is better than traditions random methods in terms of processing the
    geometry graphics operation.
    Previous published investigations have employed the WebDeGrator system to
    establish molecular computer modeling for the docking process. This study
    demonstrates examples in protein folding kinetics and drug docking computations,
    and successfully applies the Lyapunov function and molecular dynamics to help
    determine the system stability. Optimal solutions, molecular docking and protein
    folding kinetics are also discussed herein. This work integrates various research fields
    to find advanced and novel solutions to problems in bioinformatics. The combination
    of biology, information, system, and chemistry will be a powerful CADD strategy in
    the future.
    Table of Content ACKNOWLEDGMENTS                      i
    TABLE OF CONTENTS                      ii
    LIST OF FIGURES                        viii
    LIST OF TABLES                         x
    CHAPTER 1
    INTRODUCTION:1
    1.1. Introduction 1
    1.2. Literature Survey3
    1.3. Merits and Contribution 7
    1.4. Organization of Dissertation 9
    CHAPTER 2
    DRUG-RECEPTOR INTERACTION IN GEOMETRY, ENERGY AND ACTIVITY 10
    2.1 System Framework 10
    2.1.1 Docking benchmark12
    2.2 Problems with CADD13
    2.3 Drug Docking Flowcharts14
    2.3.1 Drug docking14
    2.3.2 Identifying active sites on receptors16
    2.4 Flowchart in Producing the Drug Candidate19
    2.5 Protein Folding is Important to Receptor for Drug Docking23
    2.5.1 Protein folding problem23
    2.5.2 Distributed molecular dynamics computation24
    2.6 Molecular Mechanics and Dynamics (MM and MD)26
    2.6.1 Anatomy of a Molecular Mechanics Force-Field27
    2.6.2 Molecular interaction forces and secondary bonds in Minimum Energy Experiment 3-2 with C2H2X2 Molecular Compound28
    2.7 AMBER Force Field Related to Parameter and Potential Energy Calculation29
    2.8 Drug-Receptor Interaction34
    2.8.1 Drug-receptor interactions and docking free energy calculations34
    2.8.2 Drug-receptor affinity: agonists and antagonists35
    2.8.3 Drug receptor theories excerpt37
    2.8.4 Receptor types38
    2.9 Seven Major Types of Drug-Receptor Interactions41
    2.9.1 Drug-receptor bonding41
    CHAPTER 3
    PROTEIN FOLDING SIMULATION FOR RECEPTOR-BASED DRUG DOCKING VIA ENERGY MINIMUM THEOREM46
    3.1 Protein Folding for Finding Active Sites on Receptors46
    3.1.1 Protein folding is important to receptor for drug docking46
    3.1.2 Influence of protein folding in drug design48
    3.1.3 Protein folding and disease49
    3.2 Molecular Folding with Energy Minimum via Simulation Force Field50
    3.2.1 Molecular substructure matching algorithm51
    3.2.2 Force field simulation and scoring function53
    3.2.3 Example 3-1: Force field simulation and scoring function (C2H4OX3)54
    3.3 Global Stability in an Energy Minimum Location56
    3.3.1 Example 3-2: Minimum energy experiments (C2H2X2)60
    3.3.2 Example 3-3: Comparison of results between complete and incomplete molecular folding task63
    3.3.3 Reduced distance matrix order65
    3.3.4 Example 3-4: Reduced Laplace's theorem65
    3.3.5 Langvin equation67
    3.4 Dynamics Docking System Analysis Based on Lyapunov Stability Theorem68
    3.5 Lyapunov First Method (The indirect method)69
    3.5.1 Example 3-5: Stability of infinite small perturbation motion in docking system with n molecular particles69
    3.5.2 Example 3-6: Applying Lyapunov to eliminate some points with local minimum energy72
    3.6 Lyapunov Second Method (The direct method)74
    3.6.1 Example 3-7: Construction of Lyapunov function74
    3.6.2 Example 3-8:H2O (potential energy)76
    3.7 Discriminating Among Lyapunov Stability Types76
    3.8 The Lyapunov Exponent78
    3.8.1 Physical significance of the Lyapunov exponent
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  • Hung-Yuan Chung(ÁéÂE·½)
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    Date of Submission 2007-01-18

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