drug discovery lpu
TRANSCRIPT
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Introduction• In the past most drugs have been discovered either by
identifying the active ingredient from traditionalremedies or by serendipitous discovery.
• But now we know diseases are controlled at moleculand physiological level.
• Also shape of an molecule at atomic level is wellunderstood.
• Information of Human Genome
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10,000COMPOUNDS
250COMPOUNDS 5 COMPOUNDS
~6.5 YEARS ~7 YEARS ~1.5 YE
DRUGDISCOVERY
PRECLINICAL
CLINICAL TRIALS FDREVIE
Drug Discovery &Development-Timeline
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Drug Discovery
• Drugs Discovery methods: – Random Screening – Molecular Manipulation – Molecular Designing – Drug Metabolites – Serendipity
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TargetSelection
• Cellular andGeneticTargets
• Genomics
• Proteomics
• Bioinformatics
LeadDiscovery
• Synthesis andIsolation
• CombinatorialChemistry
• Assaydevelopment
• High-ThroughputScreening
MedicinalChemistry
• LibraryDevelopment
• SAR Studies
• In SilicoScreening
• ChemicalSynthesis
In VitroStudies
• Drug AffinityandSelectivity
• Cell DiseaseModels
• MOA
• LeadCandidateRefinement
In VivoStudies
• Animalmodels ofDisease States
• BehaviouralStudies
• FunctionalImaging
• Ex-VivoStudies
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Target election• Target selection in drug discovery is defined as the
decision to focus on finding an agent with a particulbiological action that is anticipated to have therapeuutility — is influenced by a complex balance of sciemedical and strategic considerations.
• Target identification: to identify molecular targetare involved in disease progression.
• Target validation : to prove that manipulating themolecular target can provide therapeutic benefit forpatients.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Target electionBiochemical Classes of Drug Targets
G-protein coupled receptors - 45%
enzymes - 28%
hormones and factors - 11%
ion channels - 5%
nuclear receptors - 2%
Techniques for Target Identification
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Cellular & Genetic Targets:Involves the identification of the function of a potential therapeudrug target and its role in the disease process.
For small-molecule drugs, this step in the process involves identifof the target receptors or enzymes whereas for some biapproaches the focus is at the gene or transcription level.
Drugs usually act on either cellular or genetic chemicals inknown as targets, which are believed to be associated with disease.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:The study of genes and their function. Genomics aiunderstand the structure of the genome, including the mapgenes and sequencing the DNA.
Seeks to exploit the findings from the sequencing of the hand other genomes to find new drug targets.
Human Genome consists of a sequence of around 3 nucleotides (the A C G T bases) which in turn probably 35,000 – 50,000 genes.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Proteomics:It is the study of the proteome, the complete set of proproduced by a species, using the technologies of large – separation and identification.
It is becoming increasingly evident that the complexity of biosystems lies at the level of the proteins, and that genomics alonnot suffice to understand these systems.
It is also at the protein level that disease processes become manand at which most (91%) drugs act.
Therefore, the analysis of proteins (including protein-protein, prnucleic acid, and protein ligand interactions) will be utmost impoto target discovery.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Cellular &Genetic Targets
Genomics
Proteomics
Bioinformatics
Bioinformatics:Bioinformatics is a branch of molecular biology that involves extensive analbiological data using computers, for the purpose of enhancing biological res
It plays a key role in various stages of the drug discovery process including
target identification
computer screening of chemical compounds and
pharmacogenomics
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Synthesis andIsolation
CombinatorialChemistry
AssayDevelopment
HighThroughputScreening
Lead Discovery:
• Identification of small molecule modulatoprotein function
• The process of transforming these into higcontent lead series.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Synthesis andIsolation
CombinatorialChemistry
AssayDevelopment
HighThroughputScreening
Synthesis and Isolation :• Separation of mixture• Separation of impurities• In vitro chemical synthesis• Biosynthetic intermediate
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Synthesis andIsolation
CombinatorialChemistry
AssayDevelopment
HighThroughputScreening
Combinatorial Chemistry:Rapid synthesis of or computer simulatio
of large no. of different but structurallyrelated molecules• Search new leads• Optimization of target affinity &
selectivity.• Reduce toxicity and eliminate side effe
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Synthesis andIsolation
CombinatorialChemistry
AssayDevelopment
HighThroughputScreening
Assay Development• Used for measuring the activity of a drug.• Discriminate between compounds.• Evaluate:
• Expressed protein targets.•
Enzyme/ substrate interactions.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Synthesis andIsolation
CombinatorialChemistry
AssayDevelopment
HighThroughputScreening
High throughput screening:• Screening of drug target against selection o
chemicals.• Identification of highly target specific
compounds.
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
LibraryDevelopment
SAR Studies
In SilicoScreening
ChemicalSynthesis
Medicinal Chemistry:• It’s a discipline at the intersection of synthet
organic chemistry and parmacology.• Focuses on small organic molecules (and n
on biologics and inorganic compounds)• Used in
•
Drug discovery (hits)• Lead optimization (hit to lead)• Process chemistry and development
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
LibraryDevelopment
SAR Studies
In SilicoScreening
ChemicalSynthesis
SAR Studies:• Helps identify pharmacophore• The pharmacophore is the precise section o
the molecule that is responsible for biologactivity
• Enables to prepare more active compound• Allow elimination of excessive functionali
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
LibraryDevelopment
SAR Studies
In SilicoScreening
ChemicalSynthesis
In silico screening:• Computer simulated screening of chemica• Helps in finding structures that are most lik
to bind to drug target.• Filter enormous Chemical space
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
LibraryDevelopment
SAR Studies
In SilicoScreening
ChemicalSynthesis
Chemical Synthesis:• Involve production of lead compound in
suitable quantity and quality to allow largescale animal and eventual, extensive humaclinical trials
• Optimization of chemical route for bulkindustrial production.
• Suitable drug formulation
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Drug Affinityand Selectivity
Cell DiseaseModels
MOA
Lead CandidateRefinement
In Vitro Studies:• (In glass) studies using component of organism i.e. test tu
experiments• Examples-
• Cells derived from multicellular organisms• Subcellular components (Ribosomes, mitochondria)• Cellular/ subcellular extracts (wheat germ, reticuloc
extract)• Purified molecules (DNA,RNA)
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Drug Affinityand Selectivity
Cell DiseaseModels
MOA
Lead CandidateRefinement
In Vitro Studies:
Advantages:•
Studies can be completed in short period of time.• Reduces risk in post clinical trials• permits an enormous level of simplification of the s• investigator can focus on a small number of compon
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Drug Affinityand Selectivity
Cell DiseaseModels
MOA
Lead CandidateRefinement
Drug affinity and selectivity• Drug affinity is the ability of drug to bind to its biologi
target (receptor, enzyme, transport system, etc.)
• Selectivity- Drug should bind to specific receptor site ocell (eg. Aspirin)
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Drug Affinityand Selectivity
Cell DiseaseModels
MOA
Lead CandidateRefinement
• Isogenic human disease models - are a family of cells tselected or engineered to accurately model the genetics of a spepatient population, in vitro
• Stem cell disease models -Adult or embryonic stem cellsor induced to carry defective genes can be investigated iunderstand latent molecular mechanisms and disease characteri
Cell disease models
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Drug Affinityand Selectivity
Cell DiseaseModels
MOA
Lead CandidateRefinement
• Optimizing chemical hits for clinical trial is commonly r
to as lead optimization • The refinement in structure is necessary in order to impro
• Potency• Oral Availability• Selectivity• pharmacokinetic properties• safety (ADME properties)
Lead Candidate refinement
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Animal models ofDisease States
BehaviouralStudies
FunctionalImaging
Ex-Vivo Studies
In vivo studies
• Its experimentation using a whole, living
organism.• Gives information about,
• Metabolic profile•
Toxicology• Drug interaction
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Animal models ofDisease States
BehaviouralStudies
FunctionalImaging
Ex-Vivo Studies
Animal models of disease state• Test conditions involving induced disease
injury similar to human conditions.• Must be equivalent in mechanism of cause• Can predict human toxicity in 71% of the
cases.•
Eg. SCID mice-HIVNOD mice- Diabetes
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Animal models ofDisease States
BehaviouralStudies
FunctionalImaging
Ex-Vivo Studies
Behavioural Studies• Tools to investigate behavioural results of drugs.• Used to observe depression and mental disorders.• However self esteem and suicidality are hard to indu• Example:
• Despair based• Reward based• Anxiety Based
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Animal models ofDisease States
BehaviouralStudies
FunctionalImaging
Ex-Vivo Studies
Functional Imaging:• Method of detecting or measuring changes
metabolism, blood flow, regional chemicalcomposition, and absorption.• Tracers or probes used.• Modalities Used-
• MRI• CT-Scan
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Target Selection
Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Viv
Studie
Animal models ofDisease States
BehaviouralStudies
FunctionalImaging
Ex-Vivo Studies
Ex-Vivo Studies:• Experimentation on tissue in an artificial
environment outside the organism with theminimum alteration of natural conditions.• Counters ethical issues.• Examples:
• Measurement of tissue properties• Realistic models for surgery
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Clinical trials:• Set of procedures in medical research and
drug development to study the safety andefficacy of new drug.
• Essential to get marketing approval fromregulatory authorities.
• May require upto 7 years.
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase 0:• Recent designation, also known as human micro-do
studies.• First in human trials, conducted to study exploratory
investigational new drug.• Designed to to speed up the development of promisi
drugs.• Concerned with-
• Preliminary data on the drug’s pharmacodyand pharmacokinetics
• Efficacy of pre-clinical studies.
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:• Clinical Pharmacologic Evaluation• First stage of testing in human subjects.• 20-50 Healthy Volunteers• Concerned With:
–
Human Toxicity. – Tolerated Dosage Range – Pharma-cology/dynamics
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:Types of Phase-I Trials• SAD (Single Ascending Dose)• MAD (Multiple Ascending Dose)• Food effect
h
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase II:• Controlled Clinical Evaluation.•
50-300 Patients• Controlled Single Blind Technique• Concerned With:
– Safety –
Efficacy – Drug Toxicity – Drug Interaction
h
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase III:• Extended Clinical Trials.•
Most expensive & time consuming.• 250-1000 Patients.• Controlled Double Blind Technique.• Concerned With:
–
Safety, Efficacy – Comparison with other Drugs – Package Insert
Ph IV
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Target Selection
LeadDiscovery
MedicinalChemistry
In VitroStudies
In VivStudie
Phase-I
Phase-II
Phase-III
Phase-IV
Phase IV:• Post Marketing Surveillance.• Designed to detect any rare or long-term
adverse effects.• Adverse Drug Reaction Monitoring.• Pharmacovigilance.
DRUG Drug Discovery &
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10,000COMPOUNDS
250COMPOUNDS 5 COMPOUNDS
~6.5 YEARS ~7 YEARS ~1.5 YE
DRUGDISCOVERY
PRECLINICAL
CLINICAL TRIALS FDREVIE
Drug Discovery &Development-Timeline