Computational Approaches to Nuclear Receptors From Computational Simulation to In Vivo Experiments

191 Pages·2012·3.768 MB·English

RSC Drug Discovery
Edited by Pietro Cozzini and Glen E Kellogg
Computational Approaches to
Nuclear Receptors
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Computational Approaches to Nuclear Receptors
RSC Drug Discovery Series
Editor-in-Chief
ProfessorDavidThurston,LondonSchoolofPharmacy,UK
SeriesEditors:
DrDavidFox,PfizerGlobalResearchandDevelopment,Sandwich,UK
ProfessorSalvatoreGuccione,UniversityofCatania,Italy
ProfessorAnaMartinez,InstitutodeQuimicaMedica-CSIC,Spain
ProfessorDavidRotella,MontclairStateUniversity,USA
AdvisortotheBoard:
ProfessorRobinGanellin,UniversityCollegeLondon,UK
TitlesintheSeries:
1:Metabolism,PharmacokineticsandToxicityofFunctionalGroups
2:EmergingDrugsandTargetsforAlzheimer’sDisease;Volume1
3:EmergingDrugsandTargetsforAlzheimer’sDisease;Volume2
4:AccountsinDrugDiscovery
5:NewFrontiersinChemicalBiology
6:AnimalModelsforNeurodegenerativeDisease
7:Neurodegeneration
8:GProtein-CoupledReceptors
9:PharmaceuticalProcessDevelopment
10:ExtracellularandIntracellularSignaling
11:NewSyntheticTechnologiesinMedicinalChemistry
12:NewHorizonsinPredictiveToxicology
13:DrugDesignStrategies:QuantitativeApproaches
14:NeglectedDiseasesandDrugDiscovery
15:BiomedicalImaging
16:PharmaceuticalSaltsandCocrystals
17:PolyamineDrugDiscovery
18:ProteinasesasDrugTargets
19:KinaseDrugDiscovery
20:DrugDesignStrategies:ComputationalTechniquesandApplications
21:DesigningMulti-TargetDrugs
22:NanostructuredBiomaterialsforOvercomingBiologicalBarriers
23:Physico-ChemicalandComputationalApproachestoDrugDiscovery
24:BiomarkersforTraumaticBrainInjury
25:DrugDiscoveryfromNaturalProducts
26:Anti-InflammatoryDrugDiscovery
27:NewTherapeuticStrategiesforType2Diabetes:SmallMolecules
28:DrugDiscoveryforPsychiatricDisorders
29:OrganicChemistryofDrugDegradation
30:ComputationalApproachestoNuclearReceptors
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ComputationalApproachestoNuclear
Receptors
Edited by
Pietro Cozzini
Molecular Modelling Laboratory, Department of General and Inorganic
Chemistry, University of Parma, Parma, Italy
Email: [e-mail]
Glen E. Kellogg
Virginia Biotech 1, Virginia Commonwealth University, Richmond, VA, USA
RSC Drug Discovery Series No. 30
ISBN: 978-1-84973-364-9
ISSN: 2041-3203
A catalogue record for this book is available from the British Library
# The Royal Society of Chemistry 2012
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Preface
Nuclear receptors (NRs) are evolutionary conserved proteins that are
expressed in the animal kingdom. The wide-ranging family of NRs contains
more than 150 members that are represented by both steroidal and non-
steroidal receptors and by a multitude of orphan receptors, whose
physiologically relevant ligands have not yet been identified. Many of these
proteinsact,infact,asintracellularligand-inducibletranscriptionfactorsable
to respond to endogenous and exogenous chemicals regulating gene expres-
sion. These factors affect a surprisingly diverse variety of functions, such as
reproductive development, detoxification of foreign substances and fatty acid
metabolism.
While many proteins are defined as ‘druggable targets’, i.e., proteins for
which thebiological functionofasignificantfraction offamily membershave
been successfully modulated by small molecule drugs, NRs perhapsshould be
thought of as nutriable targets since they respond to intracellular metabolites
and xenobiotics such as drugs and dietary agents. Both metabolites and
xenobiotics bind to the E domain located at the carboxy terminus of the
receptors, often referred to as the ligand binding domain (LBD), whose
sequence varies substantially between NRs, but whose structure is well
conserved.
Of particular and increasing importance, molecules able to bind NRs are
defined as endocrine-disrupting chemicals (EDCs) since they are able to
interfere with the physiological function of hormonal systems, thus affecting
the health of humans and also domesticated and wild animals, causing
developmental, reproductive and metabolic diseases. Although many EDCs
are xenobiotics, derived by industrial processes and released into the
environment (i.e., pesticides, plasticizers, flame retardants, organotins,
alkylphenols, dioxins, polychlorinated biphenyls, etc.) or present in food as
RSCDrugDiscoverySeriesNo.30
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EditedbyPietroCozziniandGlenE.Kellogg
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vi Preface
flavoring, coloring, preservative or other additives, many others are naturally
occurring (e.g., phyto- and mycoestrogens) that are present in plants or fungi
as part of their defensive mechanism against physical and biological stresses.
WhetherexposuretotheEDCsisviatheenvironmentorviathefoodchain,it
is usually persistent and could be potentially harmful, as in the case of
xenobiotics, and/or beneficial, as for the phytoestrogens.
Industrializedandagriculturalareasaretypicallypollutedwithawiderange
of chemicals spread into air, soil and groundwater. Hence there are many
people who are particularly and largely irreversibly exposed to these toxic
compounds with higher risks for developing reproductive and/or endocrine
dysfunctions. By dietary and environmental exposure, EDCs can affect the
endocrine system by (i) mimicking natural hormones, (ii) antagonizing their
actionor(iii)modifyingtheirsynthesis,metabolismandtransport.Mostofthe
reportedharmfuleffectsofEDCsareattributedtotheirinterferencewithNR-,
hormone-like-mediated signaling.
However, the understanding of NRs on a molecular level is made much
more difficult by their intrinsic flexibility and plasticity. The LBD binding
sites are particularly plastic and dynamic, often dramatically changing
conformation upon binding of their ligand. This affects both experimental
approaches and computational approaches that probe (and exploit for drug
discovery, etc.) the structure of nuclear receptors. Our goal in this book is to
give to the reader a collection of viewpoints on the study of NRs with
computationalapproaches.Itisfarbeyondthescopeofthisvolumetosupply
exhaustive answers to all the questions about NRs – these are extremely
complex systems!
Inthefirstchapter,LorenzettiandNarcisodepictthefunctionsofNRsand
the links between the environment and human organisms to show how NRs
can act as mediators of the action of endocrine-active compounds.
In Chapter 2, Safo, Kellogg and Cozzini discuss how to use the available
structural data as a platform for computational studies on NRs by reviewing
theavailabledataandexplainingthebenefitsandlimitationsofthesedatawith
respect to the suite of computational approaches.
Thefollowingchapter,byDalPalu`,Dovier,FogolariandPontelli,describes
how constraint logic programming can be used as an ab initio technique to
study the structure and the flexibility of proteins. Here, it is applied to NRs.
Next, Spyrakis, Barril and Luque show the utility of molecular dynamics
techniques in understanding the movements of NRs, in both high- and low-
flexibility domains.
AsNRsareveryimportanttargetsfordrugsandfoodadditives,inChapter
5, Abagyan, Chen and Kufareva describe screening/docking approaches for
the prediction of small-molecule binding to NRs.
Bosma and Appell introduce quantum chemical approaches for studying
estrogenic toxins in Chapter 6. They also describe how quantum mechanical
approachescanbeusedtogenerateQSARdescriptors forvirtualscreeningof
drugs and food additives.
Preface vii
ArnattandZhang’schapterillustratesanexampleofhomologymodelingto
buildastructuremodelforfurthercomputationalinvestigations.Inparticular,
theyattempttocharacterizetheligandbindingmodeintheGprotein-coupled
estrogen receptor (GPER).
Because computational predictions can only be truly validated with real
‘wet’experiments,thechapterbyDellaTorreandMaggidescribesapplications
of in vivo tests using reporter bioluminescent mice to test and verify in silico
predictions.
Finally, in the last chapter, Dall’Asta, Faccini and Galaverna illustrate an
importantapplicationofusingcomputationaldiscoverytools.Theyshowhow
with in silico predictions at molecular models for estrogen receptors, new
potential pollutants can be identified and, with these predictions, new
chemosensors for food safety can be developed.
Pietro Cozzini
Glen E. Kellogg

Contents
Chapter1 NuclearReceptors:ConnectingHumanHealthtotheEnvironment 1
StefanoLorenzettiandLauraNarciso
1.1 Introducing Nuclear Receptors 1
1.2 Linking the Environment to the Human Organism:
Nuclear Receptors as Mediators of the Action of
Endocrine-active Compounds (EACs) 2
1.3 How Nuclear Receptors Work 2
1.4 Environmental Chemicals and Adverse Effects on
Human Health 13
1.5 Reproductive Diseases and Fertility 15
1.5.1 Testicular Dysgenesis Syndrome and
Spermatogenesis 15
1.5.2 Female Dysfunctions and EACs/EDCs 16
1.6 Obesity and Obesogens 18
1.7 Conclusion 19
References 19
Chapter 2 The Experimental 3D Structure of Nuclear Receptors. A
Starting Point for Computational Investigations? 23
Martin K. Safo, Glen E. Kellogg and Pietro Cozzini
2.1 Introduction 23
2.2 Flexible Proteins 25
2.2.1 Experimental Determination of Structure 25
2.2.2 Computational Tools and Challenges 27
2.3 Nuclear Receptors 30
2.3.1 A Closer Look at Structure and Function 30
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ComputationalApproachestoNuclearReceptors
EditedbyPietroCozziniandGlenE.Kellogg
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