Computational Approaches to Nuclear Receptors

by Cozzini, Pietro; Kellogg, Glen E.

• ISBN13: 9781849733649
• ISBN10: 1849733643
• Format: Hardcover
• Copyright: 2012-11-02
• Publisher: Royal Society of Chemistry

Summary

Nuclear receptors (NR) are ligand-induced activated transcription factors that are involved in numerous biological processes. Since the 1990's when the first structures were determined by means of X ray diffraction, the number of NR structures has increased considerably. Moreover several "omics" projects (genomics, pharmcogenomics and proteomics) have opened up great opportunities for the discovery of new targets, the characterization of abnormal protein patterns, the selection of "tailored" drugs and the evaluation of drug efficacy even with a lack of structural data. Furthermore, structure-based drug design, computational methods for in silico screening and nanobiotechnology- based tools are simplifying this time-consuming and money-intensive research of lead compounds and, possibly, new drugs. Biological interactions such as those that occur between a protein and ligand are concerted events where flexible molecules interact. Thus understanding flexibility of large molecules or biological complexes is of primary importance to help define the right model to approximate the reality for drug discovery, virtual screening, food safety analysis, etc. NRs are known as flexible targets, with many structural similarities, in particular for their Ligand Binding Domain: these similarities could be assumed to share behavioural qualities that belong to this class of compounds. Thus to supply a possible, complete and exhaustive answer to questions about the behaviour of NRs, their interactions with new potential drugs, endocrine disruptors such as animal and human food toxins, food additives or industry residuals, it is mandatory to approach the problem from a different point of view: a molecular modelling approach, steered synthesis, and in vitro and in vivo tests, etc. The aim of this book is to provide a state of the art review on investigations into Nuclear Receptors.

Table of Contents

Nuclear Receptors: Connecting Human Health to the Environment	p. 1
Introducing Nuclear Receptors	p. 1
Linking the Environment to the Human Organism: Nuclear Receptors as Mediators of the Action of Endocrine-active Compounds (EACs)	p. 2
How Nuclear Receptors Work	p. 2
Environmental Chemicals and Adverse Effects on Human Health	p. 13
Reproductive Diseases and Fertility	p. 15
Testicular Dysgenesis Syndrome and Spermatogenesis	p. 15
Female Dysfunctions and EACs/EDCs	p. 16
Obesity and Obesogens	p. 18
Conclusion	p. 19
References	p. 19
The Experimental 3D Structure of Nuclear Receptors. A Starting Point for Computational Investigations?	p. 23
Introduction	p. 23
Flexible Proteins	p. 25
Experimental Determination of Structure	p. 25
Computational Tools and Challenges	p. 27
Nuclear Receptors	p. 30
A Closer Look at Structure and Function	p. 30
Survey of Current Experimental Structural Data	p. 31
Mechanism of Action: Insight from Ligand Binding	p. 33
Issues for Structure-based Drug Design in Nuclear Receptors	p. 35
References	p. 36
Protein Structure Analysis with Constraint Programming	p. 40
Introduction	p. 40
A Constraint Programming Primer	p. 41
Constraint Satisfaction Problems	p. 42
Search	p. 44
Constraint Optimization Problems	p. 45
Constraint Programming-based Applications	p. 45
Protein-related Space Models	p. 47
Lattice Space Models	p. 50
Off-lattice Space Models	p. 53
Conclusion and Future Directions	p. 56
Acknowledgements	p. 57
References	p. 57
Molecular Dynamics: a Tool to Understand Nuclear Receptors	p. 60
Nuclear Receptors: Overview of the Ligand Binding Domain	p. 60
Molecular Dynamics and Protein Flexibility	p. 64
Prediction of Binding Affinities by Free Energy Calculations	p. 65
Exploring Pathways and Mechanism of Drug Binding	p. 66
Enhanced Sampling Techniques	p. 67
Ligand Binding to Nuclear Receptors	p. 70
Ligand Recognition and Specificity	p. 70
Ligand Unbinding	p. 74
Allosterism	p. 77
Final Remarks	p. 79
Acknowledgements	p. 79
References	p. 80
Docking, Screening and Selectivity Prediction for Small-molecule Nuclear Receptor Modulators	p. 84
Introduction	p. 84
Chemicals Targeting Nuclear Receptors	p. 87
Chemical Specificity: from Highly Specific to Highly Promiscuous	p. 87
Agonists, Antagonists, SNuRMs	p. 90
Analysis of Cross-reactivity	p. 91
Nuclear Receptor Ligand-binding Domains	p. 93
Structural Coverage	p. 93
Structural Basis of Agonism and Antagonism	p. 93
Computational Prediction of Nuclear Receptor Modulators	p. 97
Improving the Docking and Scoring Accuracy to Ligand-binding Domains	p. 97
Ligand-derived Atom Property Fields from Co-crystal Structures as Activity Predictors	p. 102
Prediction of Ligand Selectivity and Polypharmacology	p. 104
Acknowledgements	p. 106
References	p. 106
Quantum Chemical Studies of Estrogenic Compounds	p. 110
Introduction	p. 110
Single-molecule Density Functional Modeling and Ab Initio Modeling Studies	p. 112
Biomolecular Studies	p. 113
Chemical Properties	p. 114
Complexations	p. 115
Acknowledgements	p. 115
References	p. 115
A Nuclear G Protein-coupled Estrogen Receptor, GPER. Homology Modeling Studies Toward Its Ligand-binding Mode Characterization	p. 117
G Protein Estrogen Receptor	p. 117
Identification	p. 117
Function	p. 118
Recent Progress	p. 119
Basis as a Nuclear Receptor	p. 119
Homology Modeling	p. 120
Introduction	p. 120
General Procedure	p. 121
G Protein-coupled Receptor Homology Modeling	p. 122
G Protein Estrogen Receptor 3D Model and Ligand-binding Mode Study	p. 123
Sequence Alignment	p. 124
Template Selection	p. 126
Model Generation, Selection and Optimization	p. 128
Discussion	p. 132
References	p. 133
Reporter Bioluminescent Mice to Test Computational Studies	p. 138
Introduction	p. 138
Screening of Compounds Active Through the ER Using the ERE-Luc Mouse	p. 140
Study of the Effects of Estrogenic Compounds on Brain ER Activity	p. 141
Spatio-temporal Assessment of the Estrogenic Effects of Natural and Synthetic Compounds	p. 142
Conclusion	p. 143
Acknowledgements	p. 144
References	p. 144
From Computational Simulations on Nuclear Receptors to Chemosensors for Food Safety	p. 146
Cyclodextrins an Overview	p. 146
Structure and Properties of CDs	p. 147
CD Inclusion Complexes	p. 149
Cyclodextrins as Chemosensors: Recognition Based on Spectral Changes	p. 152
Modification of Absorption Spectra by CDs	p. 152
Induced Circular Dichroism	p. 152
Fluorescence Enhancement	p. 153
Cyclodextrin Derivatives: Strategies for Chemical Modification	p. 153
The Chemistry for Modification of CDs	p. 154
Cyclodextrins as Chemosensors for Food Diagnostics	p. 155
Cyclodextrin-Mycotoxin Complexation: a Case Study in the Food Safety Field	p. 155
Mycotoxins: General Information	p. 155
Applications of CDs to the Analysis of Mycotoxins Having Native Fluorescence	p. 158
Cyclodextrins as Selectors for the Development of Rapid Fluorimetric Assays	p. 159
Chemosensing: a Molecular Modeling-driven Strategy	p. 160
References	p. 163
Subject Index	p. 167
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