Small Molecule Drug Discovery: Methods, Molecules and Applications PDF
Preview Small Molecule Drug Discovery: Methods, Molecules and Applications
Small Molecule Drug Discovery Methods, Molecules and Applications Andrea Trabocchi Department of Chemistry "Ugo Schiff" University of Florence Sesto Fiorentino, Florence Italy Elena Lenci Department of Chemistry "Ugo Schiff" University of Florence Sesto Fiorentino, Florence Italy Elsevier Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates Copyright©2020ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyany means,electronicormechanical,includingphotocopying,recording,oranyinformation storageandretrievalsystem,withoutpermissioninwritingfromthepublisher.Detailson howtoseekpermission,furtherinformationaboutthePublisher’spermissionspolicies andourarrangementswithorganizationssuchastheCopyrightClearanceCenterandthe CopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyright bythePublisher(otherthanasmaybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand experiencebroadenourunderstanding,changesinresearchmethods,professional practices,ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafety andthesafetyofothers,includingpartiesforwhomtheyhaveaprofessional responsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,or editors,assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasa matterofproductsliability,negligenceorotherwise,orfromanyuseoroperationofany methods,products,instructions,orideascontainedinthematerialherein. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-818349-6 ForinformationonallElsevierpublicationsvisitourwebsiteat https://www.elsevier.com/books-and-journals Publisher:SusanDennis AcquisitionEditor:EmilyMMcCloskey EditorialProjectManager:KelseyConnors ProductionProjectManager:SreejithViswanathan CoverDesigner:AlanStudholme TypesetbyTNQTechnologies Contributors MichelleR. Arkin SmallMoleculeDiscoveryCenterandDepartmentofPharmaceuticalChemistry, University ofCalifornia San Francisco, San Francisco, CA,UnitedStates; Buck Institute for Research on Aging, Novato, CA, United States Andrea Basso Department ofChemistry and IndustrialChemistry,University of Genova, Genova, Italy Pietro Capurro Department ofChemistry and IndustrialChemistry,University of Genova, Genova, Italy StuartJ. Conway Department ofChemistry,Chemistry Research Laboratory,University ofOxford, Oxford,United Kingdom MargaridaEspadinha Research Institute for Medicines (iMed.ULisboa), Faculty ofPharmacy, Universidade de Lisboa, Lisbon, Portugal M. Isabel Garcı´a-Moreno University ofSeville, Seville, Spain Jose´ M. Garc´ıaFerna´ndez InstituteforChemicalResearch(IIQ),CSICeUniversityofSeville,Seville,Spain Kamal Kumar Max Planck InstituteofMolecular Physiology,Dortmund,Germany; Aicuris Antiinfective Cures GmbH,Wuppertal, Germany Elena Lenci DepartmentofChemistry“UgoSchiff”,UniversityofFlorence,SestoFiorentino, Florence, Italy Qingliang Li NationalCenter for Biotechnology Information,NationalLibrary ofMedicine, NationalInstitutes ofHealth,Besthesda,MD 20894, United States Jose´ L. Medina-Franco DepartmentofPharmacy,SchoolofChemistry,UniversidadNacionalAuto´noma de Me´xico, Mexico City,Mexico CarmenOrtiz Mellet University ofSeville, Seville, Spain xi xii Contributors Amy Trinh Pham SchoolofPharmacy,HealthSciencesCampus,UniversityofWaterloo,Waterloo, ON, Canada PraveenP.N. Rao SchoolofPharmacy,HealthSciencesCampus,UniversityofWaterloo,Waterloo, ON, Canada Fernanda I. Saldı´var-Gonza´lez DepartmentofPharmacy,SchoolofChemistry,UniversidadNacionalAuto´noma de Me´xico,Mexico City, Mexico Elena M. Sa´nchez-Ferna´ndez University ofSeville, Seville, Spain Maria M.M. Santos Research Institutefor Medicines (iMed.ULisboa),FacultyofPharmacy, Universidade de Lisboa,Lisbon,Portugal Arash Shakeri SchoolofPharmacy,HealthSciencesCampus,UniversityofWaterloo,Waterloo, ON, Canada Andrea Trabocchi DepartmentofChemistry“UgoSchiff”,UniversityofFlorence,SestoFiorentino, Florence,Italy Chris G.M. Wilson SmallMoleculeDiscoveryCenterandDepartmentofPharmaceuticalChemistry, University ofCalifornia San Francisco, San Francisco, CA, United States Foreword The discovery of new drugs is an endeavor of high scientific demand and societal relevance. It requires interdisciplinary research spanning the life sciences, chemis- try,pharmcology,andevenmaterialscience.Itbenefitsmankindbecausethetreat- mentofdisease is one ofsocieties’mosturgentdemands toscience. Amongthepharmacopoeiaavailabletous,smallmoleculeshistoricallyaremost prevalent, and they form the largest group of new chemical entities in medicinal chemistry research to this very day. Undoubtedly biologicals, in particular anti- bodies, have gained major importance and are here to stay, but it is also evident thatsmallmoleculedrugs willremaintobeofhighestrelevanceindrugdiscovery inthe foreseeablefuture. Hencethesciencethatunderliesthediscoveryanddevelopmentofnewbioactive small molecules that can be considered drug candidates and that may inspire new approachestothetreatmentofdiseaseisofutmostimportanceandcallsforcontin- uous introduction of newmethods and principles. ThisnecessityunderliesthearticlescompiledinthebookeditedbyAndreaTra- bocchi and Elena Lenci. Collectively the authors shine light on a very impressive ensembleofsomeofthemostrelevanttopicsincontemporarymedicinalchemistry and drug discovery. These include chemical synthesis, cheminformatics, and bio- physicalandcomputationalmethodsandhighlightindividualcasestudiesfocusing onsomeofthegreatestchallengesinthisscience,asforinstanceAlzheimerdisease. The Editors have chosen the topics wisely and with deep insight into drug dis- covery. Thereby the book not only gives an overview of recent developments, it also guides the reader to the frontiers of medicinal chemistry research. It will be bothentertainingtoreadandeducativesuchthatitwillbeofinteresttotheprofes- sionalskilledintheart,aswellastonewcomerstothefield,inparticular,advanced graduate andpostdoctoral students. Ihopethatthisbookwillfindwidespreadinterestfrompractitionersinmedicinal chemistryandsimplycuriousscientiststryingtogetaglimpseatandanunderstand- ingof the science thatdrivessmall molecule drugdiscovery. Herbert Waldmann Max Plank Instituteof Molecular Physiology Dortmund, Germany September 2019 xiii Preface Theidentificationofnovelmolecularentitiescapableofspecificinteractionsrepre- sents a significant challenge in early drug discovery. Despite the success of bio- pharmaceuticals, small molecules still dominate the market, being more than 95% of the top 200 most prescribed drugs in 2018. Small molecules are low- molecular-weightorganiccompoundsthatincludenaturalproductsandmetabolites, as well as drugs and other xenobiotics. The entire drug discovery process has changedalotduringthelastdecadesduetothedifficultiesinfindingnewleadcom- poundsforallthose“undruggable”targetsandforaddressingcomplexoncologyand CNSdiseases.Therationaldesignofligandsisstillapowerfulapproach,especially in combination with computer-aided methods when the biological target is well- defined and structurally known. Nevertheless, new synthetic methods able to generate high-quality chemical libraries have been exploited over the last decades tomeettheneedofimprovingthequalityandquantityofsmallmoleculesforbio- logical screenings. Since the synthetic efforts characterized by the trial-and-error approach of the 1980s and combinatorial chemistry of the 1990s, new attitudes arenowgainingwideattentioninsyntheticchemistryforsmallmoleculedrugdis- covery,inordertomaximizethequalityoflibrariesandreducingthewasteofgener- atingandscreeningrandomunnecessarycompounds.Newfrontiersinthesynthesis of small molecule libraries have been explored. Diversity-Oriented Synthesis has proven to be very effective to access large areas of the chemical space, primarily through the creation of many distinct molecular scaffolds. Also, Biology-Oriented Synthesis has been conceived with the purpose of taking inspiration from nature to select promising molecular scaffolds being related to natural products in terms ofbiologicaloutput.Today,animportantpartofmodernmedicinalchemistryisrep- resented by computer-aided methods, for rational drug design (i.e, virtual screening), and for the smart design of small molecule libraries. As the number of publiclyaccessible biologicaldataisrapidlyincreasing,chemoinformaticsisgain- ingrelevance as atool for developing better chemical libraries. Thebookisorganizedinthreeparts,exploringselectedtopicsonsmallmolecule drugdiscoveryonkeysyntheticandscreeningmethods,representativesmallmole- culecategories,andselectedbiomedicalapplications.Thefirstpartencompassesthe methodsforthesynthesis,structureclassification,andbiologicalevaluationofsmall molecules. Specifically, Chapter 1 reports an in-depth overview of strategic ap- proaches for the achievement of small molecules, and Chapter 2 gives a thorough accountaboutmostrelevantchemicalreactionsforbuildingsmallmolecules.Chap- ters3 and4report the chemoinformatictoolstoassess chemical diversityofsmall moleculelibrariesandvirtualscreeningmethods,respectively.Chapter5concludes the first part on methods discussing screening approaches and biophysics of small molecules. In the second part, representative small molecule classes derived from natural products are reported. Chapter 6 describes the principles and applications of small molecule peptidomimetics, and Chapter 7 reports the chemistry of sp2- xv xvi Preface iminosugarswithinthefieldofcarbohydrates.Chapter8outlinesthesynthesisand structural features of small molecules characterized by spiroacetal moiety, and Chapter9reportsthecasestudyofcentrocountinsasnatureinspiredindoloquinoli- zines.Thethirdpartcontainstwoselectedcasestudiesaboutthesuccessfulapplica- tion of small molecules in biomedical research. Chapter 10 deals with PPIs as therapeutic targets for anticancer drug discovery and describes the case study of MDM2andBETbromodomaininhibitors,andChapter11isanaccountofthedis- covery of small molecules for the treatmentofAlzheimer disease. These presentations have been conceivedfor a broad readership and should in- terestnotonlythosereaderswhocurrentlyworkinthefieldoforganicandmedicinal chemistry addressing drug discovery, but also those who are considering this approachinthefieldofchemicalbiology,takingadvantageoftheuseofsmallmole- cule as chemical probes for dynamically interrogating biological systems and for investigating potential drug targets. We hope these Chapters will stimulate further advances in the ever-developing field ofsmallmolecule drug discovery. AndreaTrabocchi Elena Lenci Florence, September 2019 Abbreviations (TR)-FRET Time-resolvedfluorescenceresonanceenergytransfer 2D Two-dimensional 3D Three-dimensional ACD Availablechemicalsdirectory ACE Angiotensin-convertingenzyme ACh Acetylcholine AChE Acetylcholinesterase ACN Acetonitrile AcOH Aceticacid AD Alzheimerdisease ADME Absorption-distribution-metabolism-excretion ADP Adenosinediphosphate AIDS Acquiredimmunodeficiencysyndrome ALK Anaplasticlymphomakinase AlphaScreen Amplifiedluminescentproximityhomogeneousassay AMBER AssistedModelBuildingwithEnergyRefinement ANS Anthocyanidinsynthase APDS/TRP Alanine-proline-aspartate-serine/threonine-arginine-proline ApoA1 ApolipoproteinA-1 APP Amyloidprecursorprotein APT1 Acylproteinthiosterase1 APV Amprenavir AR Androgenreceptor AS/MS Affinityselectionfollowedbymassspectrometry ATP Adenosinetriphosphate B/C/P Build/couple/pair BACE-1 Beta-siteamyloidprecursorproteincleavingenzyme1 BAL Backboneamidelinker BBB Blood-brainbarrier BET Bromodomainandextraterminaldomain Bcl-X B-celllymphoma L BCPs Bromodomain-containingproteins BEDROC BoltzmannenhanceddiscriminationofROC BIOS Biology-orientedsynthesis BLI Bio-layerinterferometry BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BRCA Breastcancergene BRD Bromodomain BRET Bioluminescenceresonanceenergytransfer BSA Bovineserumalbumin BZD Benzodiazepine CAN Cericammoniumnitrate xvii xviii Abbreviations CAS Catalyticactivesite CBD Condition-baseddivergence CCR2 ChemokineReceptortype2 CCR5 ChemokineReceptortype5 CDC Cross-dehydrogenativecouplings CDK ChemistryDevelopmentKit CDKs Cyclin-dependentkinases CDP Consensusdiversityplot CETP Cholesterylestertransferprotein CETSA Cellularthermalshiftassay ChE Cholinesterase CHI Chalconeisomerase CHS Chalconesynthase CLL B-cellchroniclymphocyticleukemia clogP Calculatedoctanol/waterpartitioncoefficient CMC Criticalmicelleconcentration CNS Centralnervoussystem COPD Chronicobstructivepulmonarydisease COX Cyclooxigenase cAMP Cyclicadenosinemonophosphate cGMP Cyclicguanosinemonophosphate CPA Chiralphosphoricacid CPAs CarboxypeptidasesA Crm1 Chromosomeregionmaintenance1 Cryo-EM Cryogenicelectronmicroscopy CS Castanospermine CSA Camphorsulphonicacid CSP Chemicalshiftperturbation CSR Cyclicsystemrecoverycurves CuAAC Cu-catalyzedAzideAlkyneClick CYP3A4 CytochromeP4503A4 DIPEA N,N-Diisopropylethylamine DCE Dichloroethane DCM Dichloromethane DCN 1,4-Dicyanonaphthalene DDQ Dichlorodicyanobenzoquinone DECLs DNA-encodedchemicallibraries DEEP-STD Differentialepitopemapping-STD DIAD Diisopropylazodicarboxylate DLS Dynamiclightscattering DMAP 4-Dimethylaminopyridine DMEDA 1,2-Dimethylethylenediamine DMF N,N-Dimethylformamide DMPU N,N0-dimethyl-N,N0-propyleneurea DMSO Dimethylsulfoxide DNA Deoxyribonucleicacid DNJ Deoxynojirimycin DNP DictionaryofNaturalProducts
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