Principles ofDrug Discovery
MODERN DRUG DISCOVERY PROCESS
Prof SaurabhGupta
PYQ Que.
Explain the stagesinvolved in modern drug discoveryprocess.
(summer 2019)
Introduction
Drug discovery is therapeutically useful in treating and curing a disease.
Modern Drug Discovery Process is a process of identifyinga compound therapeutically
useful in treating and curing adisease.
It Involves the identification of :
¸ Candidates
¸ Synthesis
¸ Characterization
¸ Screening and
¸ Assays for therapeutic efficacy.
It is an Expensive process due to the high costs of R&D and human clinical tests.
The average total costperdrug developmentvaries from US $ 897 million to US$ 1.9
billion.
Stepsin ModernDrugDiscovery
Step1:TargetIdentification
• A drug target is the specific binding site of a drug
throughwhichthe drug exerts itsaction.
• Characteristicsof Target are studied
• The drug target is a receptor, normallya protein.
• The receptor structure change when the Compound
binds to receptor.
• Due to change in the receptor structure various
physiological responsesoccur and induce regulationof
the cell, organ, tissue, or body status.
• Small moleculesbinding to the receptorsare drugs.
Step2:Targetvalidation
• Target validation is a process by whichthe predicted molecular target ( protein or nucleic acid) is verified
• it prove that manipulating the moleculartarget can provide therapeutic benefit forpatients.
• Target validationprocess might include following steps:
¸ Discovering a receptor of interest.
¸ Valuating its potential as a target
¸ Designing a bioassay to measure biological activity.
¸ Constructinga high-throughput screen.
¸ Performing screening to find hits.
¸ Evaluatingthe hits
• Biochemical classes of drug target
¸ G-Protein coupledreceptors-45%
¸ Enzymes-28%
¸ Hormones and factors-11%
¸ Ion channels -5%
¸ Nuclearreceptors -2%
Step3:Leaddiscovery
• Lead is a compound that shows possibilities as a treatment for a
disease and may leads the development of new drug
• lead generation phase, help to predict the possible profile of new
drugs in patients.
• The compounds selected are called “leads".
• Between 5 and 50000 compounds are examined in the laboratory,
of which only 100 to 200 are perfected in order to be tested on
systems in vitro and in vivo.
Step4:Leadoptimization
• Molecules are chemicallymodified in order to obtain compounds withsuitable properties to
become a drug.
• Lead optimization is a process that begins witha compound thatdisplays anbiological action and
ends withthe identification ofthe best analog.
• Leads are characterized with respect to pharmacodynamic such as efficacy and potency in vitro
and in vivo, Physiochemical properties, pharmacokinetic properties,and toxicological aspects.
• Potency- refers to the amount ofdrug required for its specific effect to occur.
• Efficacy - measures the maximumstrengthof the effect itself,at saturating drug concentrations.
• Pharmacokinetics - Itexplains about"What the bodydoes to the drug".Itoften divided into areas
examining the extent and rate of adsorption,distribution, metabolism, and excretion(ADME).
• Pharmacodynamic- It determines the biochemical and physiological effects of drugs,the
mechanismof drug action and the rela
about "What the drug does to the body".tionship betweendrug concentrationand effect. It explains
Step5:Pre-clinicaldevelopment
• The pre-clinical developmentincludes the following:
¸ developlarge scale synthesis
¸ animal safetystudies
¸ carcinogenicitytests
¸ drug delivery
¸ eliminationand metabolism studies
¸ drug formulation experiments
¸ dose-ranging studies in animals.
Wide ranging dosages ofthe compounds are introduced to the cell line or animal inorder toobtain
preliminaryefficacyand pharmacokinetic information.
¸
Step6:Clinicaldevelopment
• Treatment trials:
test experimental treatments or a newcombination ofdrugs.
• Prevention trials:
look for ways to prevent a disease or prevent it fromreturning.
• Diagnostic trials:
find better testor procedures for diagnosing a disease.
• Screening trials:
test methods of detecting diseases.
• Qualityof life trials:
explore ways to improve comfort& quality of life for individuals with a chronic illness
Reference:
• Principles of Drug Discovery by Padmaja kore first edition
• Chapter 41- Modern drug discovery and Development ScienceDirect
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