USING MOLECULAR SIMILARITY ANALYSIS FOR STRUCTURE-ACTIVITY RELATIONSHIP STUDIES A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Weiguo Fan December 2012 Dissertation written by Weiguo Fan B.S., Wuhan University, P. R. China, 1989 M.A., Kent State University, USA, 2001 Ph. D, Kent State University, USA, 2012 Approved by _______Johnnie W. Baker_____________, Chair, Doctoral Dissertation Committee _______Chun-che Tsai________________, Co-chair, Doctoral Dissertation Committee _______Robert Walker_________________, Members, Doctoral Dissertation Committee _______Ye Zhao_____________________ _______Olena Piontkivska______________ Accepted by _______Javed I. Khan________________ , Chair, Department of Computer Science _______Raymond Craig________________, Dean, College of Arts and Sciences ii TABLE OF CONTENTS LIST OF FIGURES ...................................................................................................... VII LIST OF TABLES ........................................................................................................... X ACKNOWLEDGEMENTS ........................................................................................... XI CHAPTER 1 INTRODUCTION ..................................................................................... 1 1.1 Synopsis .................................................................................................................... 1 1.2 Overview of dissertation contents ............................................................................. 5 1.3 My contributions ....................................................................................................... 6 CHAPTER 2 HISTORY BACKGROUND .................................................................... 7 2.1 TOPSIM development history .................................................................................. 7 2.2 Structural similarity analysis ................................................................................... 12 CHAPTER 3 MOLECULAR SIMILARITY ANALYSIS .......................................... 15 3.1 Molecular descriptors .............................................................................................. 15 3.2 Labeled graphs ........................................................................................................ 17 3.3 Compatibility graphs, isomorphism, edge induced isomorphism. .......................... 18 3.4 Finding MaCS algorithms ....................................................................................... 21 3.5 Find the largest clique algorithm ............................................................................. 29 3.6 Some historical works such as eliminating the redundant MaCS ........................... 34 3.7 Molfiles. .................................................................................................................. 36 iii 3.8 How TOPSIM generates the molfile ....................................................................... 38 3.9 Topological symmetry problem .............................................................................. 42 3.10 Summary about the algorithms used by TOPSIM .................................................. 43 CHAPTER 4 TOPSIM 4.0 WINDOWS BASED INTERFACE ................................. 50 4.1 The original interface of TOSPIM .......................................................................... 50 4.2 TOPSIM 4.0 ............................................................................................................ 53 CHAPTER 5 TOPSIM 4.0 WEB BASED INTERFACE ............................................ 55 5.1 What is PHP? .......................................................................................................... 55 5.2 The web version of TOPSIM – Web TOPSIM ....................................................... 57 5.3 Summary ................................................................................................................. 60 CHAPTER 6 STRUCTURE-ACTIVITY MAP (SAM) AND STRUCTURAL ORDERING (SO)................................................................................................ 61 6.1 Introduction ............................................................................................................. 61 6.2 Structure-activity maps (SAMs) and the basic descriptors ..................................... 61 6.3 Topological distance (TD) and structural ordering (SO) ........................................ 63 6.4 A special case of structural orderings ..................................................................... 64 6.5 Algorithm to find the structural ordering ................................................................ 65 6.6 Drug prediction flowchart ....................................................................................... 69 CHAPTER 7 TOPSIM APPLICATION I: 2-D SAMS AND SO ANALYSIS .......... 72 7.1 Introduction ............................................................................................................. 72 7.2 NAB vs.TEAC SAM ............................................................................................... 73 iv 7.3 NAB vs. RSA SAM ................................................................................................ 83 7.3.1 Intra-ground observation ............................................................................... 88 7.3.2 Inter-group observations and structural orderings ........................................ 90 7.4 NAB-Anti HIV activity SAM ................................................................................. 92 7.4.1 SAMs analysis ............................................................................................... 94 7.4.2 Intra-group observations ............................................................................. 101 7.4.3 Inter-group observations and structural orderings ...................................... 103 7.5 NAB-anti COX-2 activity SAM ............................................................................ 105 7.5.1 SAMs Analysis ............................................................................................ 106 7.5.2 Intra-Group Observations ............................................................................ 108 7.5.3 Inter-Group Observations and Structural Ordering ..................................... 114 CHAPTER 8 TOPSIM APPLICATION II: 3D SAMS ............................................. 118 8.1 Introduction ........................................................................................................... 118 8.2 Biological data ....................................................................................................... 119 8.3 SAMs analysis ....................................................................................................... 120 8.3.1 COX-1 inhibition activity analysis. ............................................................. 120 8.3.2 COX-2 inhibition activity analysis. ............................................................. 125 8.3.3 SI(COX-1/COX-2) analysis ........................................................................ 126 8.3.4 3-layer SAM ................................................................................................ 127 8.3.5 3-D (dimensional) SAM .............................................................................. 127 8.4 Summary ............................................................................................................... 136 v CHAPTER 9 MICS – MINIMUM COMMON SUPERSTRUCTURE ................... 137 9.1 Introduction ........................................................................................................... 137 9.2 Generating MiCS ................................................................................................... 143 9.3 An example for the MiCS ..................................................................................... 147 9.4 Isolated atoms included in MiCS .......................................................................... 148 9.5 Improvements on generating MiCS algorithm. ..................................................... 150 CHAPTER 10 CONCLUSIONS AND FUTURE WORK ........................................ 153 10.1 Conclusions ........................................................................................................... 153 10.2 Future works .......................................................................................................... 158 APPENDIX A USER GUIDE TO TOPSIM 4.0 ......................................................... 161 APPENDIX B A USER GUIDE TO WEB TOPSIM ................................................. 172 TOPSIM Output Molfile .......................................................................................... 174 Prepare the Input File ............................................................................................. 175 Use Web TOPSIM .................................................................................................... 177 REFERENCES .............................................................................................................. 183 vi LIST OF FIGURES Figure 2.1, Pharmacophore modeling: a topological approach ........................................ 14 Figure 3.1, Example of molecular descriptors .................................................................. 17 Figure 3.2, Molecules K001 and K002 ............................................................................