Drug Discovery lpu

8/9/2019 Drug Discovery lpu

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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


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


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


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


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


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



AssayDevelopment


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



AssayDevelopment


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



AssayDevelopment


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



AssayDevelopment


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


Cell DiseaseModels

MOA


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


Cell DiseaseModels

MOA


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


Cell DiseaseModels

MOA


• 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


Cell DiseaseModels

MOA


• 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


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


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


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


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

Drug Discovery lpu

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