History of computers in pharmaceutical research & development

In this presentation I have mentioned whatever the possible relevant content required for the title.

Citation Is done at the end of slide.

Content is up to date & true to my belief.

Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- [email protected]

1. HISTORY OF COMPUTERS
IN PHARMACEUTICAL
RESEARCH
&
DEVELOPMENT
PRESENTED BY :-ANURAG PANDEY
M.PHARM (PHARMACEUTICS)
CADD
INSTITUTE OF PHARMACY, NIRMA UNIVERSITY
UNDER THE GUIDANCE OF :-DR. TEJAL MEHTA
PROFESSOR & HOD AT,
INSTITUTE OF PHARMACY, NIRMA UNIVERSITY

2. DETAILED OUTLINE ABOUT HISTORY
•Today,computersaresoubiquitousinpharmaceuticalresearchanddevelopmentthatitmay
behardtoimagineatimewhentherewerenocomputerstoassistthemedicinalchemistor
biologist.
•Aquarter-centuryago,thenotionofacomputeronthedeskofeveryscientistandcompany
managerwasnotevencontemplated.Now,computersareabsolutelyessentialforgenerating,
managing,andtransmittinginformation.
•Theaimofthischapteristogiveabriefaccountofthehistoricaldevelopment.Itisastoryof
ascendancyandonethatcontinuestounfold.
•Owingtothepersonalinterestandexperienceoftheauthors,theemphasisinthis
presentationisonusingcomputersfordrugdiscovery.Buttheuseofcomputersinlaboratory
instrumentsandforanalysisofexperimentalandclinicaldataisnolessimportant.

3. •Asscienceadvancedscientistbeganunderstandingtherelationbetweenthechemical
structureofamoleculeanditsmolecularpropertiesincludingbiologicalactivity.On
thebasisofmolecularpropertiesofanymoleculethenitsstructurecanbepredicted&
investigatedinlaboratory.
•Alsoatthesametimeconceptsofhowadrugexertsitsbiologicalactivitythrough
bindingtosomereceptorinthebodystemmedfromFischer’slockandkey
hypothesis.
•“Quantummechanics”tookaleapforwardinexplainingthemovementofelectronsin
moleculesandhowelectronicstructureimpactsbiologicalactivity.
•Inthe1950’spapersbegantobepublishedmathematicallyrelatingchemical
structuretobiologicalactivity.Thesedevelopmentsfinallyledtotheintroductionto
QSAR(QuantitativeStructureActivityRelationships)whichbasicallyassigned
moleculardescriptorsindescribingbiologicalactivity.Thesemoleculardescriptorsare
nothingbutacalculatedorexperimentalnumericalvaluethatdescribesthechemical
structureofthatmolecule.QSARweretheresultoftheengineeringdevelopmentof
computersandtheiruse.Thusthecomputer,whichwasinitiallydesignedtobeusedin
themilitaryandforaccountingapplications,graduallybecameatoolforscientific
innovation.

4. •Todaycomputationalbiologystandsattheforefrontofinnovationandhasreduced
thetimeforfindingpotentialcandidatesbymatchingmolecularstructure
databasesagainsttargetmoleculesandfindinganappropriatematch
thusgeneratingaleadcompound.Withtheadvancementincomputer
technologyandfasterandmoreefficientsupercomputerslikethe“BlueGene”and
“RedStorm”beingmade,thetaskisonlymadesimpler.
•Intheearly1960sdrugdiscoverywasby“trialanderror”.Atthattime
thereweretwomainsourcesoftherapeuticcompounds.Thesmallerpipelinewas
naturalproductssuchasplantswithmedicinalpropertiesandsoilmicrobes.The
majorsourcewasclassicalmedicinalchemistry.The‘chemistsatthattime
manuallyreadliteratureofproductspatentedbycompetitorsandused
theircreativityandexpertisetosynthesizetherapeuticallyactive
compounds’.Thesecompoundswouldthenbetestedbyinhousemicrobiologists
andbiochemists.Thecompoundswerenotonlytestedagainstitstargetbutalso
screenedforbioactivityagainstothertargetsforwhichresearchwasbeingconducted
atthattime.Themostpotentcompounddiscoveredledtoaseriesofotherstructures
whichweretestedhenceleadingtothecreationofatablecomparingthepotencyand
activity,whichfinallyledtoonecompoundthatcouldbeeffectivelycalledthedrug
andafterdevelopmentcalledapharmaceuticalproduct.However,thesemethods
involvedtimeandcostandwereinaccurate.

5. •CompaniessuchasAbbott,Schering-Plough,UpjohnandDow
Chemical’stooktheinitiativetoexploreusingcomputersfordrug
discovery.Theseinitiativesinvolvedeitheraddingresourceswithcomputer
proficiencyortrainingin-housescientistsonthenewmethodology.
Oneofthefirstbreak-throughincomputationaldrugdiscoverywasat
Lillywhichrevealedtherelationshipbetweenthecalculatedelectronic
structureofbeta-lactamringofcephalosporinsandantibacterial
activity.Eventhoughsomeofthecompaniesinitiatedtheseefforts,someof
thesecompanieslostoutastheyquittheseeffortsduetolackof
managementsupport.ItwasLilly,whosepersistencepaidoffasit
establisheditsbaseinsuchexpertise.Thecompaniesatthattimeinvested
inhardwareandsoftwarefromthemoneytheygainedfromthesaleoftheir
products.WidelyusedmodelsatthattimeincludedtheIBM360andthe370
seriesandinputmethodsslowlyadvancedfrompunchcardstodumb
terminals(terminalsorPCsthathadnolocalprocessingcapability).

6. •SoftwarewasstillwritteninFORTRAN,followedbythewellknownMMPI
programusedformolecularmechanics.Sincemolecularmechanicsseemsto
predicttheorganicchemicalstructuresmoreaccuratelythanquantummechanics
(withbondlengthspredictedcorrectlyupto0.01À),thisprogramwasan
importantdevelopment.Withthesedevelopmentsthepharmaceuticalindustrybegan
transitioningtousingmolecularmechanics,QSARandstatisticsratherthanrestrictingto
quantummechanics.
•Howeveratthebackofallthisawarragedbetweenthemedicinalandcomputational
chemists.Thecomputationalchemistsemphasizedthatcomputationallyitwaseasierto
changeanitrogenatomtocarbonoranyotherelementortoattachasubsistentatany
positioninwhateverstereochemistrywhichwouldmakethecompoundmoreactive.It
waseasytochangeasixmemberringtoafivememberringandsoon

7. •Lillytookapositivestepinthisopeningcommunicationchannelsbetweenthetwogroups
andorganizedaseriesofworkshopsforthemedicinalchemiststooperateoncomputational
programstoperformcalculationsonmolecules.ThiswasfollowedbyMerckwhich
conductedasimilarworkshop.Despitetheseinitiativesthemedicinalchemistswereslowto
acceptwhatcomputerswereabletoprovide.Sometimestheywouldgotothecomputational
chemistsforhelpwithsomeoftheresearchcomputationallylikeactivitylistingofasetof
compoundsandifthecomputationalmethodsfailedthemedicinalchemistswouldstart
dismissingtheideaofcomputationalchemistryasawhole.
•Thetruthisthatcomputationaltechniquesshouldbeconsideredlikeanotherapparatusina
lab.Sometimeitwouldgiveapositiveresult,andsometimefailliketherestofthe
experimentalmethods.
•Inthe1970stwonewcomputerresourceswerelaunchednamelytheCambridge
StructuralDatabase(CSD)andthePDB(ProteinDataBank).Computationalchemists
foundthisasaboonasthesedatabaseswouldyieldmoretherapeuticallyactive
compoundsasmorecompoundsweredepositedintothem.
•Theadvancementcameinthe1980s.Thepharmaceuticalcompaniesnotedthe
developmentoftheIBMpersonalcomputer(PC),butithadDOS,whichmadeitdifficultto
use.

8. •In1984,theAppleMacintoshwasintroducedwhichsetanewstandardofuserfriendlinessto
thecomputer.Thesemachinesweregreatatwordprocessing,graphicsandmanagingsmall
laboratorydatabasesandsuddenlyallmedicinalchemiststookalikingtoit.Alsotherewere
advancementsonthesoftwarefrontwhichmademostmedicinalchemistsenthusiasticabout
computers.Onewastheelectronicmail.Thissawgreatadvancementincommunicationand
alsowiththisonecouldeasilyconnecttoothercomputersandtapintolargedatabasesasthe
cablingandnetworkingcapabilityadvanced.
•ThesecondimportantdevelopmentwasdevelopmentofcertainsoftwarelikeChemDraw
whichallowedchemiststoquicklycreatetwodimensionalchemicaldiagramswhichcouldbe
cutandpastedintoreports,articleandpatents.
•Thethirdimportantadvancementwastheabilitytoview3Dstructuresofcompoundsona
computerscreenusingeithertheballandstickmodelorspacefillingrepresentationsof
3Dmolecularstructuresandthisintroducedawholenewfieldof“moleculargraphics”.

9. •Onalargerscalepharmaceuticalcompaniesstartedbecomingawareofthepotentialfor
computeraidedmethodsofdrugdesign.Accordingtoasurveyafewyearslater,48
chemicalandpharmaceuticalcompaniesintheUSwereusingcomputeraided
moleculardesignmethods.
•Between1975and1985thenumberofcomputationalchemistsemployedbythese
chemistsincreasedfrom30to150whichweremorethandoublingeveryfiveyears.
•The1990ssawtheresultsoftheeffortsputinthe1980swhichyieldedalargenumberof
NCEs(newchemicalentities)reachingthepharmaceuticalmarketplace.

10. •“Supercomputersbegantoappearinthescenetooasfasterprocessingandnumber
crunchingbecameanecessity.Initiallynocompanywantedtomakeaninvestmentina
supercomputeranditseemsthatthemarketwouldneverbreakopen.”
•ItwasCEOofCrayresearchwhostrategicallytookaboldstepofpayingavisittothe
CEOofLillytoofferasupercomputertothecompanyatanirresistibleprice.His
strategypaidoff,asnotonlyLillypurchasedthesupercomputerbutother
pharmaceuticalcompanieslikeMerck,Bristol-MyersSquibb,MarionMerrellDow,
JohnsonandJohnsonandBayereitherpurchasedorleasedasupercomputerfromCray
researchtostaycompetitiveinthepharmaceuticalmarketplace.
•Withcomputationaldrugdiscoverybecomingmoreanmoreimportant,theattitudetowards
thecomputationalchemistschanged,somuchsothatLillyandothercompaniesmade
computationalchemistsco-inventorsonpatentsifacomputationalchemisthadcontributedto
thediscovery.
•Thesefactorsledtothegrowthofthecomputationalscientistpoolandcomputershave
becomeanindispensablefactorintheprocessofdrugdiscoveryanddevelopmentever
since.

11. HISTORY
OF
COMPUTATIONAL CHEMISTRY
1925,
warner
heisenberg, Max
born & pascal
jordandeveloped
matrix
mechanics
1951
UNIVAC-1
st
Commercial
comp. was
built
1927,
Douglas hartee
published self-
consistent field
method
1930
Vldamir
fock
formulated
hartee-Fock
theory
1947
ENIAC first
general
purpose
comp was
built
1950
Clemens
roothaan
formulated
LCAO
theory
1971,
commercially
available intel
4004
microprosser
1964,
hohenberg&
Walter kohn
introduced
density
functional
theory
1955 1
st
ab
iniitio
calculation
on ‘large’
molecules
1970
john pople
introduced
Gaussian
software
1925,
walter& fritz
published 1
st
calculation
on chemical
bonding

13. IMPORTANCE OF COMPUTERS IN
PHARMA INDUSTRY

15. SUMMARY

16. REFERENCES
•REVIEW ARTICLE
•History of Computers in Pharmaceutical Research and Development by
ClinSkill| Dec 19, 2017 | Pharmaceutical Research
•BOOK
•Computer Applications in Pharmaceutical Research and Development –
“S.Ekins(Wiley, 2006) WW”.
•IMAGES TAKEN FROM GOOGLE & SOURCE OF SLIDE NUMBER 14 IS
LINKED WITH HYPERLINK INTO IT.