Drug Discovery by Design

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    Drug Discovery by DesignDrug Discovery by DesignGareth ThomasGareth Thomas

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    2.1. Introduction2.1. Introduction

    Drug discovery isDrug discovery is part luck and part structuredpart luck and part structuredinvestigationinvestigation..

    At the beginning of the nineteenth century it wasAt the beginning of the nineteenth century it was

    largely carried out by individuals but it nowlargely carried out by individuals but it nowrequires teamwork, the members of the teamrequires teamwork, the members of the teambeingbeing specialists in various fieldsspecialists in various fields, such as, such asmedicine, biochemistry, chemistry, computerisedmedicine, biochemistry, chemistry, computerised

    molecular modelling, pharmaceutics,molecular modelling, pharmaceutics,pharmacology, microbiology, toicology, physiologypharmacology, microbiology, toicology, physiologyand pathology.and pathology.

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    lead compoundslead compounds

    !he drugs used in medicine are!he drugs used in medicine aredeveloped from so"calleddeveloped from so"called leadleadcompoundscompounds#$igure 2.1%.#$igure 2.1%.

    !hese compounds were originally!hese compounds were originallydiscovered by investigating localdiscovered by investigating localfolk remedies, and natural productsfolk remedies, and natural products

    such as plants #land and marine%,such as plants #land and marine%,trees, microorganisms and animals.trees, microorganisms and animals.

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    !hese are still useful sources of lead!hese are still useful sources of leadcompounds but many are now producedcompounds but many are now producedas a result of investigations into theas a result of investigations into thenature of disease statesnature of disease states..

    &ead compounds are often unsuitable&ead compounds are often unsuitablefor clinical use because theyfor clinical use because they may bemay beeither too toic or have seriouseither too toic or have seriousunwanted side effects.unwanted side effects.

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    'owever, their structures ser'owever, their structures serveveas theas thestarting points for the synthesisstarting points for the synthesis of so"of so"called analogues, one or more of whichcalled analogues, one or more of whichmay be suitable for clinical use #$iguremay be suitable for clinical use #$igure2.1%.2.1%.

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    The approach to drug designThe approach to drug design

    !he approach to drug design!he approach to drug designdepends ondepends onthe ob(ectives of the design team.the ob(ectives of the design team.!hese ob(ectives can range from!hese ob(ectives can range from

    changing the pharmacokinetics of anchanging the pharmacokinetics of aneisting drug to designing a completelyeisting drug to designing a completelynew compound.new compound.

    In all cases the team will start byIn all cases the team will start by

    devising an outline of the intendeddevising an outline of the intendedinvestigationinvestigation..

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    $or eample, if the ob(ective is$or eample, if the ob(ective is totomodify themodify thepharmacokineticspharmacokinetics of anof aneisting drug the design team has toeisting drug the design team has todecide what structural modificationsdecide what structural modificationsneed to be investigated in order toneed to be investigated in order toachieve that ob(ective.achieve that ob(ective.

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    )n the other hand, if the ob(ective is to)n the other hand, if the ob(ective is tofind a new drug for a specific medicalfind a new drug for a specific medical

    problem the starting point is aproblem the starting point is aknowledge of the biochemistryknowledge of the biochemistryof theof thecondition and*or the microorganismcondition and*or the microorganismresponsible for the condition.responsible for the condition.

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    !his may require basic research into the!his may require basic research into thedisease"causing processdisease"causing process before initiating thebefore initiating thedrug design investigation #$igure 2.1%. !hedrug design investigation #$igure 2.1%. !heinformation obtained is used by the team toinformation obtained is used by the team todecide where intervention would be mostdecide where intervention would be mostlikely to bring about the desired result.likely to bring about the desired result.

    )nce the point of intervention has been)nce the point of intervention has beenselected the team hasselected the team has to decide on theto decide on the

    structure of a lead compound that couldstructure of a lead compound that couldpossibly bring about the required changepossibly bring about the required change..

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    Objectie !r"# $isi#%Objectie !r"# $isi#%

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    A number of candidates are usuallyA number of candidates are usuallyconsidered but the epense ofconsidered but the epense ofproducing drugs dictates that the teamproducing drugs dictates that the team

    hashas to choose only one or two of theseto choose only one or two of thesecompoundscompounds to either act as the lead orto either act as the lead ortoto bbe the inspiration for the leade the inspiration for the leadcompound.compound.

    !he final selection depends on the!he final selection depends on theeperience of the team.eperience of the team.

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    )ne approach to lead compound selection is to)ne approach to lead compound selection is tocarry out a comprehensive literature andcarry out a comprehensive literature anddatabase search to identify compounds founddatabase search to identify compounds found

    in the organismin the organism #endogenous compounds%#endogenous compounds%andandcompounds that are not found in the organismcompounds that are not found in the organism#eogenous compounds%#eogenous compounds% that have somethat have somebiological effect at the intervention site.biological effect at the intervention site.

    !hese compounds are used as leads and!hese compounds are used as leads andmodified in an appropriate manner.modified in an appropriate manner.

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    &ea$ 'ompo"%$ se(ectio%&ea$ 'ompo"%$ se(ectio%

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    )i#"re 2.1. The #e%era( steps i% the $esi#%

    of a %e* $r"#.

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    +odern approaches to lead compound+odern approaches to lead compounddiscovery includediscovery include combinatorialcombinatorialchemistry and computer modelingchemistry and computer modelingtechniquestechniques ..

    !he former uses a simultaneous multiple!he former uses a simultaneous multiplesynthesis technique to produce largesynthesis technique to produce largenumbers of potential leads. !hesenumbers of potential leads. !hesepotential leads are sub(ected to rapidpotential leads are sub(ected to rapid

    high"throughput biological screening tohigh"throughput biological screening toidentify the most active leadidentify the most active leadcompounds.compounds.

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    )nce identified, these lead compounds are)nce identified, these lead compounds aresub(ect to further development.sub(ect to further development.

    omputer modeling is normally usedomputer modeling is normally used to checkto check

    whether the three"dimensional structure ofwhether the three"dimensional structure ofthe proposed lead is complementary to thatthe proposed lead is complementary to thatof its receptor domain.of its receptor domain.

    'owever, this does require a detailed'owever, this does require a detailedknowledge of the three"dimensionalknowledge of the three"dimensionalstructures of the ligand and target site.structures of the ligand and target site.

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    enantiomers and their racematesenantiomers and their racemates

    A ma(or consideration in the selectionA ma(or consideration in the selectionof a lead is its stereochemistry. It isof a lead is its stereochemistry. It isnow recognised that the biologicalnow recognised that the biological

    activities of the individualactivities of the individual enantiomersenantiomersand their racematesand their racematesmay be verymay be verydifferent.different.

    onsequently, it is necessary to e