PREFACE ........................................................ xv
ACKNOWLEDGMENTS ............................................... xix
ABOUT THE AUTHOR .............................................. xxi
SYMBOLS USED IN THIS BOOK ................................... xxiii
BOOK ABSTRACT ................................................ xxix
1. Introduction ................................................ 1
1.1. A Difficult Problem ................................... 1
1.2. An Expensive Problem .................................. 2
1.3. Where Computational Techniques are Used ............... 3
Bibliography ................................................ 5
PART I. THE DRUG DESIGN PROCESS ................................ 7
2. Properties that Make a Molecule a Good Drug ................. 9
2.1. Compound Testing ..................................... 10
2.1.1. Biochemical Assays ............................ 11
2.1.2. Cell-Based Assays ............................. 13
2.1.3. Animal Testing ................................ 14
2.1.4. Human Clinical Trials ......................... 15
2.2. Molecular Structure .................................. 16
2.2.1. Activity ...................................... 16
2.2.2. Bioavailability and Toxicity .................. 24
2.2.3. Drug Side Effects ............................. 26
2.2.4. Multiple Drug Interactions .................... 26
2.3. Metrics for Drug-Likeness ............................ 27
2.4. Exceptions to the Rules .............................. 33
Bibliography ............................................... 35
3. Target Identification ...................................... 41
3.1. Primary Sequence and Metabolic Pathway ............... 41
3.2. Crystallography ...................................... 43
3.3. 2D NMR ............................................... 44
3.4. Homology Models ...................................... 45
3.5. Protein Folding ...................................... 45
Bibliography ............................................... 46
4. Target Characterization .................................... 47
4.1. Analysis of Target Mechanism ......................... 47
4.1.1. Kinetics and Crystallography .................. 48
4.1.2. Automated Crevice Detection ................... 48
4.1.3. Transition Structures and Reaction
Coordinates ................................... 49
4.1.4. Molecular Dynamics Simulations ................ 49
4.2. Where the Target is Expressed ........................ 50
4.3. Pharmacophore Identification ......................... 50
4.4. Choosing an Inhibitor Mechanism ...................... 51
Bibliography ............................................... 52
5. The Drug Design Process for a Known Protein Target ......... 53
5.1. The Structure-Based Design Process ................... 53
5.2. Initial Hits ......................................... 55
5.3. Compound Refinement .................................. 56
5.4. ADMET ................................................ 67
5.5. Drug Resistance ...................................... 67
Bibliography ............................................... 68
6. The Drug Design Process for an Unknown Target .............. 71
6.1. The Ligand-Based Design Process ...................... 71
6.2. Initial Hits ......................................... 72
6.3. Compound Refinement .................................. 73
6.4. ADMET ................................................ 74
Bibliography ............................................... 74
7. Drug Design for Other Targets .............................. 75
7.1. DNA Binding .......................................... 76
7.2. RNA as a Target ...................................... 78
7.3. Allosteric Sites ..................................... 79
7.4. Receptor Targets ..................................... 80
7.5. Steroids ............................................. 81
7.6. Targets inside Cells ................................. 82
7.7. Targets within the Central Nervous System ............ 83
7.8. Irreversibly Binding Inhibitors ...................... 84
7.9. Upregulating Target Activity ......................... 84
Bibliography ............................................... 85
8. Compound Library Design .................................... 87
8.1. Targeted Libraries versus Diverse Libraries .......... 87
8.2. From Fragments versus from Reactions ................. 89
8.3. Non-Enumerative Techniques ........................... 90
8.4. Drug-Likeness and Synthetic Accessibility ............ 91
8.5. Analyzing Chemical Diversity and Spanning known
Chemistries .......................................... 93
8.6. Compound Selection Techniques ........................ 96
Bibliography ............................................... 99
PART II. COMPUTATIONAL TOOLS AND TECHNIQUES .................. 103
9. Homology Model Building ................................... 105
9.1. How much Similarity is Enough? ...................... 106
9.2. Steps for Building a Homology Model ................. 107
9.2.1. Step 1: Template Identification .............. 108
9.2.2. Step 2: Alignment between the Unknown and
the Template ................................. 108
9.2.3. Step 3: Manual Adjustments to
the Alignment ................................ 110
9.2.4. Step 4: Replace Template Side Chains with
Model Side Chains ............................ 111
9.2.5. Step 5: Adjust Model for Insertions and
Deletions .................................... 111
9.2.6. Step 6: Optimization of the Model ............ 112
9.2.7. Step 7: Model Validation ..................... 112
9.2.8. Step 8: If Errors are Found Iterate Back
to Previous Steps ............................ 115
9.3. Reliability of Results 116 Bibliography .............. 117
10. Molecular Mechanics ....................................... 119
10.1. A Really Brief Introduction to Molecular
Mechanics ........................................... 119
10.2. Force Fields for Drug Design 121 Bibliography ....... 123
11. Protein Folding ........................................... 125
11.1. The Difficulty of the Problem ....................... 125
11.2. Algorithms .......................................... 127
11.3. Reliability of Results .............................. 129
11.4. Conformational Analysis ............................. 130
Bibliography .............................................. 131
12. Docking ................................................... 133
12.1. Introduction ........................................ 133
12.2. Search Algorithms ................................... 135
12.2.1. Searching the Entire Space .................. 135
12.2.2. Grid Potentials versus Full Force Field ..... 137
12.2.3. Flexible Active Sites ....................... 138
12.2.4. Ligands Covalently Bound to the
Active Site ................................. 138
12.2.5. Hierarchical Docking Algorithms ............. 139
12.3. Scoring ............................................. 141
12.3.1. Energy Expressions and Consensus Scoring .... 141
12.3.2. Binding Free Energies ....................... 141
12.3.3. Solvation ................................... 144
12.3.4. Ligands Covalently Bound to the
Active Site ................................. 144
12.3.5. Metrics for Goodness of Fit ................. 144
12.4. Validation of Results ............................... 145
12.5. Comparison of Existing Search and Scoring Methods ... 146
12.6. Special Systems ..................................... 153
12.7. The Docking Process ................................. 155
12.7.1. Protein Preparation ......................... 156
12.7.2. Building the Ligand ......................... 156
12.7.3. Setting the Bounding Box .................... 157
12.7.4. Docking Options ............................. 157
12.7.5. Running the Docking Calculation ............. 158
12.7.6. Analysis of Results ......................... 158
Bibliography .............................................. 159
13. Pharmacophore Models ...................................... 161
13.1. Components of a Pharmacophore Model ................. 163
13.2. Creating a Pharmacophore Model from Active
Compounds ........................................... 164
13.3. Creating a Pharmacophore Model from the
Active Site ......................................... 166
13.4. Searching Compound Databases ........................ 167
13.5. Reliability of Results .............................. 168
Bibliography .............................................. 169
14. QSAR ...................................................... 171
14.1. Conventional QSAR versus 3D-QSAR .................... 171
14.2. The QSAR Process .................................... 172
14.3. Descriptors ......................................... 175
14.4. Automated QSAR Programs ............................. 176
14.5. QSAR versus Other Fitting Methods ................... 177
Bibliography .............................................. 178
15. 3D-QSAR ................................................... 181
15.1. The 3D-QSAR Process ................................. 182
15.2. 3D-QSAR Software Packages ........................... 184
15.3. Summary ............................................. 184
Bibliography .............................................. 184
16. Quantum Mechanics in Drug Design .......................... 187
16.1. Quantum Mechanics Algorithms and Software ........... 188
16.2. Modeling Systems with Metal Atoms ................... 191
16.3. Increased Accuracy .................................. 191
16.4. Computing Reaction Paths ............................ 193
16.5. Computing Spectra ................................... 193
Bibliography .............................................. 194
17. De novo and Other AI Techniques ........................... 197
17.1. De novo Building of Compounds ....................... 198
17.2. Nonquantitative Predictions ......................... 201
17.3. Quantitative Predictions ............................ 203
Bibliography .............................................. 205
18. Cheminformatics ........................................... 207
18.1. Smiles SLN and Other Chemical Structure
Representations ..................................... 208
18.2. Similarity and Substructure Searching ............... 209
18.3. 2D-to-3D Structure Generation ....................... 213
18.4. Clustering Algorithms ............................... 214
18.5. Screening Results Analysis .......................... 217
18.6. Database Systems .................................... 222
Bibliography .............................................. 223
19. ADMET ..................................................... 225
19.1 Oral Bioavailability ................................ 227
19.3. Blood-Brain Barrier Permeability .................... 231
19.4. Toxicity ............................................ 231
Bibliography .............................................. 234
20. Multiobjective Optimization ............................... 237
Bibliography .............................................. 240
21. Automation of Tasks ....................................... 241
21.1. Built-in Automation Capabilities .................... 241
21.2. Automation Using External Utilities ................. 243
Bibliography .............................................. 244
PART III. RELATED TOPICS ...................................... 245
22. Bioinformatics ............................................ 247
Bibliography .............................................. 251
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