Computational Toxicology

List of Contributors xvii
 
Preface xxi
 
Acknowledgments xxiii
 
Part I Computational Methods 1
 
1 AccessibleMachine Learning Approaches for Toxicology 3
Sean Ekins, Alex M. Clark, Alexander L. Perryman, Joel S. Freundlich, Alexandru Korotcov, and Valery Tkachenko
 
1.1 Introduction 3
 
1.2 Bayesian Models 5
 
1.2.1 CDD Models 7
 
1.3 Deep LearningModels 13
 
1.4 Comparison of Different Machine LearningMethods 16
 
1.4.1 Classic Machine LearningMethods 17
 
1.4.1.1 Bernoulli Naive Bayes 17
 
1.4.1.2 Linear Logistic Regression with Regularization 18
 
1.4.1.3 AdaBoost Decision Tree 18
 
1.4.1.4 Random Forest 18
 
1.4.1.5 Support Vector Machine 19
 
1.4.2 Deep Neural Networks 19
 
1.4.3 Comparing Models 20
 
1.5 FutureWork 21
 
Acknowledgments 21
 
References 21
 
2 Quantum Mechanics Approaches in Computational Toxicology 31
Jakub Kostal
 
2.1 Translating Computational Chemistry to Predictive Toxicology 31
 
2.2 Levels of Theory in Quantum Mechanical Calculations 33
 
2.3 Representing Molecular Orbitals 38
 
2.4 Hybrid Quantum and Molecular Mechanical Calculations 39
 
2.5 Representing System Dynamics 40
 
2.6 Developing QM Descriptors 42
 
2.6.1 Global Electronic Parameters 42
 
2.6.1.1 Electrostatic Potential, Dipole, and Polarizability 43
 
2.6.1.2 Global Electronic Parameters Derived from Frontier Molecular Orbitals (FMOs) 45
 
2.6.2 Local (Atom-Based) Electronic Parameters 47
 
2.6.2.1 Parameters Derived from Frontier Molecular Orbitals (FMOs) 48
 
2.6.2.2 Partial Atomic Charges 51
 
2.6.2.3 Hydrogen-Bonding Interactions 51
 
2.6.2.4 Bond Enthalpies 53
 
2.6.3 Modeling Chemical Reactions 53
 
2.6.4 QM/MM Calculations of Covalent Host-Guest Interactions 56
 
2.6.5 Medium Effects and Hydration Models

Sean Ekins, MSc, PhD, DSc has over 20 years of pharmaceutical and toxicology experience. He is the founder or co-founder of two companies and Adjunct Professor at three universities. He has been awarded 16 NIH grants as Principal Investigator. He has authored or co authored over 285 peer-reviewed papers and book chapters and edited five books with Wiley. His research is focused on collaborations to facilitate rare and neglected disease drug discovery.