Table of Contents Table of Contents ADMET Predictor Warranty & Copyright Notices OVERVIEW 1. ADMET Predictor's Interface 1.1. Interface Layouts 1.1.1. Basic Manipulations 1.1.2. Toolbar details 1.2. FILE Menu 1.3. EDIT Menu 1.4. VIEW Menu 1.5. DATA Menu 1.6. TOOLS Menu 1.7. CHEMISTRY Menu 1.8. Manipulating Structures 1.8.1. Opening a Structure File 1.8.2. Adding Structures To Spreadsheet 1.8.3. Editing Structures 1.8.4. MedChem Designer 1.8.5. Modify/Redraw 1.9. Searching the Spreadsheet 1.9.1. Search by Query 1.9.2. Search by Text 1.9.3. Find Duplicates 1.9.4. Find Tautomer Duplicates 1.10. Working with Attributes 1.10.1. Defining a Set 1.10.2. Importing Attributes 1.10.3. Adding Other Attributes 1.10.4. Compound Attributes Window 1.10.5. Viewing Atomic Properties 1.10.6. Modifying Attributes 1.10.7. Deleting Attributes 1.10.8. Transforming Attributes 1.11. Modifying the Spreadsheet Layout 1.11.1. Control Window 1.11.2. Tiled Spreadsheet 1.11.3. Move Rows 1.11.4. Insert/Delete Columns 1.11.5. Rearrange Columns 1.11.6. Resize Columns 1.11.7. Hide/Unhide Rows 1.11.8. Sort Columns 1.12. Plotting Data 1.12.1. Histograms 1.12.2. Bar charts 1.12.3. 2D Scatter Plots 1.12.4. 3D Scatter Plots 1.12.5. Confusion Matrix 1.12.6. Docking Charts 1.12.7. Copying, Printing and Exporting Data 1.12.8. Miner 3D 1.13. Preferences 1.14. HELP and Licensing 1.15. Command Line 1.15.1. Usage, Arguments and Options 1.15.2. Command Examples 1.15.3. Script File Workflows 1.15.4. Saving pKa Results 1.16. REST API 1.17. Interacting with Other Programs Pipeline Pilot KNIME Python ecosystem 2. ADMET Properties 2.1. What Makes a Good Model? 2.2. ADMET Risk 2.2.1. Absorption Risk 2.2.2. CYP Risk 2.2.3. TOX Risk 2.2.4. Adding a New Risk Model 2.2.5. Out-of-Scope Factor 2.3. Calculating ADMET Properties 2.4. PhysChem and Biopharm Properties 2.4.1. Dissociation Constant (pKa) 2.4.2. Partition Coefficients 2.4.3. Solubility, melting point and solvation 2.4.4. Permeability 2.4.5 Beyond Rule of Five Assay Models 2.4.6 Drug Diffusion in Mucus 2.5. Pharmacokinetic Properties 2.5.1. Distributional Properties 2.5.2.Clearance Classification 2.5.3. BCS/DCS Assignment 2.6. Transporter Models 2.6.1. Transporter Substrate Models 2.6.2. Transporter Km Models 2.6.3. Transporter Inhibition Models 2.7. Metabolism Models 2.7.1. Phase I: Oxidation CYP Substrate Classification CYP Sites of Metabolism CYP Enzyme Kinetics CYP Enzyme Inhibition Constant CYP Inhibition CYP Induction Aldehyde Oxidase (AOX) 2.7.2. Phase II: Glucuronidation 2.7.3. Predicting Metabolites CYPs and AOX UGTs Esterases 2.7.4. Intrinsic Clearance 2.8. Toxicity Models 2.8.1. Reproductive and Genetic Toxicity 2.8.2. Rodent Toxicity 2.8.3. Human Toxicity 2.8.4. Ecotoxicity 2.9. DILIsym Models 2.9.1. Mitochondrial Dysfunction 2.9.2. Reactive Oxygen Species 2.9.3. MRP3 2.9.4. MDR3 2.10. Descriptor Sensitivity Analysis 2.11. Structural Sensitivity Analysis 2.12. Using the Model Editor 2.13. Property Theory and Details 2.13.1. Subtleties of Multiprotic Ionization 2.13.2. Solubility in Biorelevant Media 2.13.3. Descriptor Definitions 2.13.4. Lipole Moment 2.13.5. pH-Dependent Attributes for Use in Models 3. ADMET Modeler 3.1. How to Build a Good Model 3.2. Running ADMET Modeler 3.2.1. Variable Selection 3.2.2. Selecting a Modeling Protocol Model Type Settings Test Set Selection Descriptor Selection 3.2.4. Model Settings Summary 3.2.5. Performance Grid 3.2.6. Performance Plots 3.2.7. Uncertainty and Model Selection Classification Models Regression Models 3.2.8. Exporting and Saving Models 3.3. Modeler Menus 3.4. Modeler Theory and Details 3.4.1. Modeling Methods 3.4.2. Ensembles 3.4.3. Descriptor Selection 3.4.4. Kohonen Mapping 3.4.5. Uncertainty Analysis Classification Confidence Regression Uncertainty 3.4.6. Finding the Best Ensemble 3.4.7. DELTA Models 3.4.8. Composite Models 4. MedChem Studio 4.1. CHEMISTRY Menu 4.2. Classes 4.2.1. CLASSES Menu 4.2.2. Data Spreadsheet 4.2.3. Class Generation Methods Frameworks Ring-Anchored Systems Chain-Anchored Systems Fingerprint clustering Custom Scaffolds Form One Superclass Split Into Singletons Homogeneity and Redundancy 4.2.4. Removing Molecules From a Class 4.2.5. Adding Class Attributes 4.2.6. Sorting The Classes 4.2.7. Aggregation Function 4.2.8. Comparing Classes 4.3. R Tables 4.3.1. R TABLES Menu 4.3.2. Data Spreadsheet 4.3.3. Sorting the Spreadsheet 4.3.4. Finding Subsets Using R-Groups 4.3.5. The R Group Analyzer 4.3.6. R-Table Explosion 4.4. Pairs 4.4.1. PAIRS Menu 4.4.2. Pair Generation Options 4.4.3. Data Spreadsheet 4.4.4. Pairs for Similarity Searching 4.4.5. Clustering Molecular Pairs 4.4.6. Reaction Transforms From Pairs 4.5. Keys 4.5.1. KEYS Menu 4.5.2. Data Spreadsheet 4.5.3. Key Generation Methods 4.6. Similarity Screening 4.6.1. Molecular Similarity 4.7. Molecular Libraries 4.7.1. LIBRARY Menu 4.8. Retrosynthesis score (SynthScore) 4.9. 3D Conformers 4.10. 3D Conformer Databases 4.11. 3D Similarity Screening 5. Compound Design 5.1. DESIGN Menu 5.2. AI Drug Design 5.2.1. AIDD Theory 5.3. Combinatorial Reaction 5.4. Combinatorial Transform 5.5. R List Explosion 5.6. Generate Fragments 5.7. Replace Scaffolds or R Groups 6. HTPK Simulation Module 6.1. Absorption & Bioavailability 6.2. Dose Optimization 6.3. Cp-Time Curve 6.4. Parameter Sensitivity Analysis 6.5. Advanced Simulation Parameters 6.6. Simulation Theory and Details 6.6.1. Intestinal Absorption and Bioavailability 6.6.2. Dose Optimization 6.6.3. Comparison with GastroPlus simulations 6.6.4. HIA File Format 6.7. Peff Converter 6.8. HTPK Archive Feature 6.9. HTPK Results Units 7. Tutorials and Exercises 7.1. ADMET Predictor Inputs 7.1.1. Interactive Input: SMILES 7.1.2. Interactive Input: SDF 7.1.3. Interactive Input: MOL 7.2. ADMET Predictor Outputs 7.2.1. Output: Chemistry File Formats (SDF, SMI, MOL) 7.2.2. Output: Other File Formats (TXT, XLS, CSV) 7.3. Exporting from Plots 7.3.1. Plots 7.3.2. Numerical Data 7.3.3. Special Plot: pKa Performance Graph 7.4. Customizing ADMET Risk Loading the Data Saving a Modified Lipinski Rule of 5 File Modifying the Rule for Hydrogen Bond Donors Adding Another Logical Expression to an Existing Rule Adding a New Rule Based on Molal Volume Adding New ADMET Risk Rule Models Applying and Examining the New ADMET Risk Rules Tutorial Notes, Tips and Warnings 7.5. ADMET Modeler 7.5.1. ANNE Regression Using Input Gradient Descriptor Selection Loading Molecular Structures and Calculating Properties Basic Modeler Settings Modeling Protocol ANN Settings Building Models Model Performance Exporting a Model Applying the New Predictive Model 7.5.2. ANNE Regression Using Descriptor Selection by GA Loading Data and Configuring Settings Building Models Model Performance Descriptors Examination 7.5.3. MLR Models Loading Data and Configuring Settings Building Models Model Performance Descriptors Examination 7.5.4. SVM Classification Models Loading Data and Configuring Settings Building Models Model Performance 7.5.5. ANNE Binary Classification Models Loading Data and Configuring Settings Building Models Model Performance with Confidence Analysis 7.5.6. KPLS Models Loading Data and Configuring Settings Building Models Exporting the Model 7.6. Curating Data on BACE Inhibitors Loading the Data Properties-Based Compound Filtering Cleaning the Data Scaffold-Based Compound Filtering 7.7. Building a DELTA Model 7.7.1. Loading the data 7.7.2. Global Model Predictions 7.7.3. Building a Local CLint Model 7.7.4. Constructing the DELTA Model 7.7.5. Comparing Predictive Performances 7.8. Optimizing BACE1 Inhibitors with AIDD 7.8.1. Loading the Data 7.8.2. Loading User Models 7.8.3. Selecting a Seed Molecule 7.8.4. Setting AIDD Parameters 7.8.5. Analyzing AIDD Results APPENDICES ENDNOTES GLOSSARY FILE FORMATS Structure File Formats XTK File CTK File SD File MOL File SMILES File Model File Formats Kohonen SOM (.som) ANNE Definitions (.net) ANNE Performance (.ann) SVM Definition (.svm) KPLS Definition (.kpl) PLS Definition for equations and MLR models (.pls) XGBoost model definiton file (.xgb) Other Modeler File Formats Parameters File (.prm) Log File (.log) Performance Statistics (.rms) Predicted vs Observed (.pno) Reaction Formats SMIRKS Reactions Named Reactions Encoded Reactions RXN File CRF File Query Formats SMARTS Queries The Query Wizard Encoded Queries Named-property queries Score Queries Query File (CQF Files) BIBLIOGRAPHY
