Computer Applications in Drug Discovery and Development PDF
Preview Computer Applications in Drug Discovery and Development
A volume in the Advances in Medical Technologies and Clinical Practice (AMTCP) Book Series Computer Applications in Drug Discovery and Development A. Puratchikody Anna University, India S. Lakshmana Prabu Anna University, India A. Umamaheswari Anna University, India Published in the United States of America by IGI Global Medical Information Science Reference (an imprint of IGI Global) 701 E. Chocolate Avenue Hershey PA, USA 17033 Tel: 717-533-8845 Fax: 717-533-8661 E-mail: Advances in Medical Technologies and Clinical Practice (AMTCP) Book Series Srikanta Patnaik SOA University, India Priti Das S.C.B. Medical College, India ISSN:2327-9354 Mission EISSN:2327-9370 Medical technological innovation continues to provide avenues of research for faster and safer diagnosis and treatments for patients. Practitioners must stay up to date with these latest advancements to provide the best care for nursing and clinical practices. The Advances in Medical Technologies and Clinical Practice (AMTCP) Book Series brings together the most recent research on the latest technology used in areas of nursing informatics, clinical technology, biomedicine, diagnostic technologies, and more. Researchers, students, and practitioners in this field will benefit from this fundamental coverage on the use of technology in clinical practices. Coverage • Biometrics IGI Global is currently accepting manuscripts • Clinical Data Mining for publication within this series. To submit a pro- • Nursing Informatics posal for a volume in this series, please contact our • Medical Imaging Acquisition Editors at Titles in this Series For a list of additional titles in this series, please visit: www.igi-global.com/book-series Clinical Costing Techniques and Analysis in Modern Healthcare Systems Ronald Ma (Austin Health, Australia) Medical Information Science Reference • ©2019 • 265pp • H/C (ISBN: 9781522550822) • US $235.00 (our price) Optimized Genetic Programming Applications Emerging Research and Opportunities Bahrudin Hrnjica (University of Bihac, Bosnia and Herzegovina) and Ali Danandeh Mehr (Antalya Bilim Uni- versity, Turkey) Medical Information Science Reference • ©2019 • 310pp • H/C (ISBN: 9781522560050) • US $225.00 (our price) Design and Development of Affordable Healthcare Technologies Arindam Bit (National Institute of Technology Raipur, India) Medical Information Science Reference • ©2018 • 388pp • H/C (ISBN: 9781522549697) • US $245.00 (our price) Optimizing Health Literacy for Improved Clinical Practices Vassilios E. 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Ceren Akal (Ankara University, Turkey) Medical Information Science Reference • ©2018 • 413pp • H/C (ISBN: 9781522553632) • US $265.00 (our price) Multifunctional Nanocarriers for Contemporary Healthcare Applications Md. Abul Barkat (K.R. Mangalam University, India) Harshita A.B. (K.R. Mangalam University, India) Sarwar Beg (Jubilant Generics, India) and Farhan J. Ahmad (Jamia Hamdard, India) Medical Information Science Reference • ©2018 • 602pp • H/C (ISBN: 9781522547815) • US $265.00 (our price) 701 East Chocolate Avenue, Hershey, PA 17033, USA Tel: 717-533-8845 x100 • Fax: 717-533-8661 E-Mail: Table of Contents Preface..................................................................................................................................................xii Acknowledgment................................................................................................................................ xvi Chapter 1 DrugDiscovery:CurrentStateandFutureProspects............................................................................. 1 S. Lakshmana Prabu, Anna University, India Chapter 2 ChemicalStructureDatabasesinDrugDiscovery............................................................................... 47 Pramodkumar Pyarelal Gupta, D. Y. Patil University (Deemed), India Virupaksha Ajit Bastikar, Amity University Mumbai, India Santosh Subhash Chhajed, MET Bhujbal Knowledge City, India Chapter 3 LeadOptimizationintheDrugDiscoveryProcess............................................................................... 62 S. Lakshmana Prabu, Anna University, India Rathinasabapathy Thirumurugan, Plants for Human Health Institute, USA Chapter 4 QSARandLeadOptimization.............................................................................................................. 80 N. Ramalakshmi, C. L. Baid Metha College of Pharmacy, India S. Arunkumar, Gulf Medical University, UAE Sakthivel Balasubramaniyan, Anna University, India Chapter 5 VirtualScreeningandItsApplicationsinDrugDiscoveryProcess................................................... 101 Gurusamy Mariappan, St. Mary’s College of Pharmacy, India Anju Kumari, St. Mary’s College of Pharmacy, India Chapter 6 ComputationalInvestigationofVersatileActivityofPiperine........................................................... 127 Thenmozhi Marudhadurai, Selvam College of Technology, India Navabshan Irfan, Anna University, India Chapter 7 TargetIdentifcationofHDAC8IsoformfortheTreatmentofCancer............................................... 140 A. Umamaheswari, Anna University, India A. Puratchikody, Anna University, India Sakthivel Balasubramaniyan, Anna University, India Chapter 8 MolecularModellingStudiesofNovelCOX-2Inhibitors.................................................................. 173 A. Puratchikody, Anna University, India A. Umamaheswari, Anna University, India Navabshan Irfan, Anna University, India Dharmaraj Sriram, Birla Institute of Technology and Sciences, India Chapter 9 ConstructionandAnalysisofProtein-ProteinInteractionNetwork:RoleinIdentifcationofKey SignalingMoleculesInvolvedinaDiseasePathway.......................................................................... 204 Divya Dasagrandhi, Bharathidasan University, India Arul Salomee Kamalabai Ravindran, Bharathidasan University, India Anusuyadevi Muthuswamy, Bharathidasan University, India Jayachandran K. S., Bharathidasan University, India Chapter 10 QualitybyDesigninPharmaceuticalFormulation............................................................................. 221 Sundaramurthy Vivekanandan, Bluefsh Pharmaceuticals Pvt. Ltd, India Chapter 11 TheNextGenerationSequencingTechniquesandApplicationinDrugDiscoveryand Development....................................................................................................................................... 240 Afzal Hussain, Maulana Azad National Institute of Technology, India Chapter 12 SemanticTechnologiesforMedicalKnowledgeRepresentation........................................................ 260 Shridevi S., VIT Chennai, India Saleena B., VIT Chennai, India Viswanathan V., VIT Chennai, India Compilation of References............................................................................................................... 276 About the Contributors.................................................................................................................... 325 Index................................................................................................................................................... 330 Detailed Table of Contents Preface..................................................................................................................................................xii Acknowledgment................................................................................................................................ xvi Chapter 1 DrugDiscovery:CurrentStateandFutureProspects............................................................................. 1 S. Lakshmana Prabu, Anna University, India Modernchemistryfoundationsweremadeinbetweenthe18thand19thcenturiesandhavebeenextended in20thcentury.R&Dtowardssyntheticchemistrywasintroducedduringthe1960s.Developmentofnew moleculardrugsfromtheherbalplantstosyntheticchemistryisthefundamentalscientifcimprovement. About10-14yearsareneededtodevelopanewmoleculewithanaveragecostofmorethan$800million. Pharmaceutical industriesspend thehighestpercentageof revenues,but theachievementofdesired molecularentitiesintothemarketisnotincreasingproportionately.Asaresult,anapproximateof0.01% ofnewmolecularentitiesareapprovedbytheFDA.Thehighestfailurerateisduetoinadequateefcacy exhibited inPhaseIIof thedrugdiscoveryanddevelopmentstage. Innovative technologiessuchas combinatorialchemistry,DNAsequencing,high-throughputscreening,bioinformatics,computational drugdesign,andcomputermodelingarenowutilizedinthedrugdiscovery.Thesetechnologiescan acceleratethesuccessratesinintroducingnewmolecularentitiesintothemarket. Chapter 2 ChemicalStructureDatabasesinDrugDiscovery............................................................................... 47 Pramodkumar Pyarelal Gupta, D. Y. Patil University (Deemed), India Virupaksha Ajit Bastikar, Amity University Mumbai, India Santosh Subhash Chhajed, MET Bhujbal Knowledge City, India Biologicallyactiveandapprovedmoleculeshaveattractedgreatinterestfromscientistsworkinginthe therapeuticarea.Thishasgreatlyincreasedthepressureonthepharmaandlifescienceindustryinfueling newmoleculestothemarket.Chemicalstructuredatabase,thebackboneofcheminformaticsandthe bioinformaticsindustry,haswarehousedmillionsofactiveandnon-activemolecules/ligands/derivatives ofdrugcompounds.Numerouspublicandprivatechemicaldatabasessupportthedrugdiscoveryprojects bycontributingtheirdatasourceintermsof2D,3Dstructure,andannotationreportsindevelopmentof efectivetherapeuticprojects.Inthischapter,theauthorsdiscussimportantchemicalstructuredatabases andtheirdiversedatasetutilizationindrugdiscoveryprojects. Chapter 3 LeadOptimizationintheDrugDiscoveryProcess............................................................................... 62 S. Lakshmana Prabu, Anna University, India Rathinasabapathy Thirumurugan, Plants for Human Health Institute, USA Discoveringanewdrugmoleculeagainstdiseaseisthemainobjectiveofdrugdiscovery.Leadoptimization isoneoftheimportantstepsandactsasastartingpoint.Overtheyears,ithassignifcantlychanged thedrugdiscoveryprocess.Itsmainfocusisthedevelopmentofpreclinicalcandidatesfrom“Hit”or “Lead.”Leadoptimizationcomprisesleadselectionandoptimization,drugcandidateconfrmation,and preclinicaldrugcharacterization.Leadoptimizationprocesscanimprovetheefectivenesstowardsits targetpotency,selectivity,proteinbinding,pharmacokineticparameters,andtodevelopagoodpreclinical candidate.Leadoptimizationfromhigh-throughputscreeningtoidentifcationofclinicaldrugcandidate isaseamlessprocessthatdrawsnewtechniquesforacceleratedsynthesis,purifcation,screeningfrom iterative compound libraries, validation, and to deliver clinical drug candidate with limited human resources.Inconclusion,leadoptimizationphaseisdoneunderthesuggestionthattheoptimizedlead moleculewillhaveactivityagainstaparticulardisease. Chapter 4 QSARandLeadOptimization.............................................................................................................. 80 N. Ramalakshmi, C. L. Baid Metha College of Pharmacy, India S. Arunkumar, Gulf Medical University, UAE Sakthivel Balasubramaniyan, Anna University, India Therearemanydiseasesforwhichsuitabledrugshavenotbeenidentifed.Asthepopulationincreases and the environment gets polluted, new infections are reported. Random screening of synthesized compoundsforbiologicalactivityistimeconsuming.QSARhasaprominentroleindrugdesignand optimization.Itisderivedfromthecorrelationbetweenthephysicochemicalpropertiesandbiological activity.QSARequationsaregeneratedusingstatisticalmethodslikeregressionanalysisandgenetic functionapproximation.Both2Dparametersand3Dparametersareinvolvedingeneratingtheequation. AmongseveralQSARequationsgenerated,thebestonesareselectedbasedonstatisticalparameters. Validation techniques usually verify the predictive power of generated QSAR equations. Once the developedQSARmodelisvalidatedtobegood,theresultsofthatmodelmaybeappliedtopredictthe biologicalactivityofneweranalogues.ThischapterillustratesthevariousstepsinQSARanddescribes thesignifcanceofstatisticalparametersandsoftwareusedinQSAR. Chapter 5 VirtualScreeningandItsApplicationsinDrugDiscoveryProcess................................................... 101 Gurusamy Mariappan, St. Mary’s College of Pharmacy, India Anju Kumari, St. Mary’s College of Pharmacy, India Virtualscreeningplaysanimportantroleinthemoderndrugdiscoveryprocess.Thepharmacompanies investhugeamountsofmoneyandtimeindrugdiscoveryandscreening.However,atthefnalstageof clinicaltrials,severalmoleculesfail,whichresultsinalargefnancialloss.Toovercomethis,avirtual screeningtoolwasdevelopedwithsuperpredictivepower.Thevirtualscreeningtoolisnotonlyrestricted toolsmallmoleculesbutalsotomacromoleculessuchasprotein,enzyme,receptors,etc.Thisgives aninsightintostructure-basedandLigand-baseddrugdesign.VSgivesreliableinformationtodirect theprocessofdrugdiscovery(e.g.,whenthe3Dimageofthereceptorisknown,structure-baseddrug designisrecommended).Thepharmacophore-basedmodelisadvisablewhentheinformationaboutthe receptororanymacromoleculeisunknown.InthisADME,parameterssuchasLogP,bioavailability, andQSARcanbeusedasflters.Thischaptershowsbothmodelswithvariousrepresentativeexamples thatfacilitatethescientisttousecomputationalscreeningtoolsinmoderndrugdiscoveryprocesses. Chapter 6 ComputationalInvestigationofVersatileActivityofPiperine........................................................... 127 Thenmozhi Marudhadurai, Selvam College of Technology, India Navabshan Irfan, Anna University, India Piperineisknownforitsversatiletherapeuticactivity.Ithasbeenusedforvariousdiseaseconditions(e.g., cold,cough,etc.).Piperineisanalkaloidfoundinblackpepper.Itpossessesvariouspharmacological actionslikeanti-infammatory,anti-oxidant,anti-cholinergic,andanti-cancerous.Theabove-mentioned propertieswillbestudiedbyselectingtargetproteinsCOX-2protein,angiotensinconvertingenzyme, acetylcholineesterases, and survivin using computational docking study. This chapter explains the inhibitionpropertyofpiperineagainstselectedtargetproteinfromtheresultsofdockingstudies.Based onthedockingscoresandprotein-ligandinteractions,piperinewasfoundtobindwellintheactivesite oftheselectedtargetproteins.Itensuresthebindingefcacyofpiperineagainstselectedtargetproteins. Dockingscoresandprotein-ligandinteractionsplaysanimportantroleinitstherapeuticactivity. Chapter 7 TargetIdentifcationofHDAC8IsoformfortheTreatmentofCancer............................................... 140 A. Umamaheswari, Anna University, India A. Puratchikody, Anna University, India Sakthivel Balasubramaniyan, Anna University, India Targetidentifcationhasbeenconsideredasachiefparameterindrugdiscoveryasitfullycharacterizes on-targetandof-targetefectsofdrugbinding.Cellsignalingreceptors,structuralproteins,andpost- translationalmodifcationsofhistonesbyhistonedeacetylasesarethemostwidespreadtargetsthatare progressivelybeingexplored.TheFDAapprovedhistonedeacetylasesinhibitorsandthemajorityof HDACiinandoutofclinicaltrialsbasedontheactivitiesof11isoformsoftheenzymeinnon-selective infuence approach. Unfortunately, reported HDACi does not possess a high degree of structural specifcityandultimatelylessensthetherapeuticindexwithmanydoselimitingtoxicities.Thischapter illustrateshowdiferentapproachesareincorporatedintothenovelinhibitorsdiscoverythataretruly isoform-selectiveandwhicharespecifcallyinvolvedintargetingonlyaparticularisozyme.Further,it highlightstheaspectsrelatingtoprovideawidertherapeuticindexwithanimprovedtoxicityprofleof leadlikeepigeneticmodulators. Chapter 8 MolecularModellingStudiesofNovelCOX-2Inhibitors.................................................................. 173 A. Puratchikody, Anna University, India A. Umamaheswari, Anna University, India Navabshan Irfan, Anna University, India Dharmaraj Sriram, Birla Institute of Technology and Sciences, India Molecularmodellingusestheoreticalandcomputationalchemistry,whichofersinsightintothenature of molecular systems. This chapter highlights the theoretical explanation of molecular modelling methodsanddescribesthedesigningofnoveltyrosineCOX-2inhibitorsusingmolecularmodellingas anexample.Asafrststep,fragment-baseddrugdesignisusedtodesignthenoveltyrosineanalogues andligand-baseddrugdesignsuchasQSAR,andpharmacophorewasusedtoidentifythedescriptors, ensembleofstericandelectronicfeatures,whichisresponsiblefortheselectiveCOX-2inhibition.The nextstep,structure-baseddrugdesign,wasusedtoanalysesintra-andintermolecularinteractionsin thedrugreceptorsystemtoimprovethebindingafnityandpharmacokineticproperties.Finally,the pharmacokineticandtoxicitypropertieswerepredictedquantitativelyusingrationalizationofobserved structure-activityrelationshipsandtheresultsarereported. Chapter 9 ConstructionandAnalysisofProtein-ProteinInteractionNetwork:RoleinIdentifcationofKey SignalingMoleculesInvolvedinaDiseasePathway.......................................................................... 204 Divya Dasagrandhi, Bharathidasan University, India Arul Salomee Kamalabai Ravindran, Bharathidasan University, India Anusuyadevi Muthuswamy, Bharathidasan University, India Jayachandran K. S., Bharathidasan University, India Understandingthemechanismsofadiseaseishighlycomplicatedduetothecomplexpathwaysinvolved inthediseaseprogression.Despiteseveraldecadesofresearch,theoccurrenceandprognosisofthe diseasesisnotcompletelyunderstoodevenwithhighthroughputexperimentslikeDNAmicroarrayand next-generationsequencing.Thisisduetochallengesinanalysisofhugedatasets.Systemsbiology is one of the major divisions of bioinformatics and has laid cutting edge techniques for the better understandingofthesepathways.Constructionofprotein-proteininteractionnetwork(PPIN)guidesthe modernscientiststoidentifyvitalproteinsthroughprotein-proteininteractionnetwork,whichfacilitates theidentifcationofnewdrugtargetandassociatedproteins.ThechapterisfocusedonPPIdatabases, constructionofPPINs,anditsanalysis. Chapter 10 QualitybyDesigninPharmaceuticalFormulation............................................................................. 221 Sundaramurthy Vivekanandan, Bluefsh Pharmaceuticals Pvt. Ltd, India Qualitybydesign(QbD)isasystematic,scientifc,risk-basedapproachtoproductdevelopmentand manufacturingprocesstoconsistentlydeliverthequalityproduct.Inthischapter,application,benefts, opportunities, regulatory requirements involved inqualitybydesignofpharmaceuticalproductsare discussed.Inqualitybydesignapproach,duringdevelopment,thedeveloperdefnesqualitytargetproduct profle(QTPP)andidentifescriticalqualityattributes(CQA).Criticalprocessparameters(CPP)ofunit operationswhichimpactscriticalqualityattributesneedtobeidentifedtounderstandtheimpactof criticalmaterialattributes(CMA)onqualityattributesofthedrugproduct.Qualitybydesignapproach isdefnedinICHguidelinesQ8–PharmaceuticalDevelopment,Q9–QualityRiskManagement,Q10– PharmaceuticalQualitySystem.Thischapterdescribestheimplementationofnewconceptsinqualityby designlikedesignofexperimentstoachievedesignspace,controlstrategytoconsistentlymanufacture qualityproductthroughouttheproductlifecycle.
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