A genome is an organism’s complete set of DNA or complete genetic makeup, The entire DNA complement. It describes the identity and the sequence of genes of an organism. Genomics is the study of entire genomes(structure, function, evolution, mapping, and editing of genomes) Executing the sequencing and analysis of entire human genome enables more rapid and effective identification of disease associated genes and provide drug companies with pre validated targets. Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems./ large scale study of protein and their functions. Proteomics measures protein expression directly, not via gene expression, thus achieving better accuracy. Current work uses 2-dimensional polyacrylamide gel electrophoresis(2D- PAGE) and mass spectrometry. New separation and characterization technologies, such as protein microarray and high throughput chromatography are being developed.

1. Role of Genomics and Proteomics
in Target Discovery and validation
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Presented By
Pavana K A
M.Pharm,Pharmacology
COPS,DSU

2. Genomics
• A genome is an organism’s complete set of DNA or complete genetic
makeup, The entire DNA complement. It describes the identity and
the sequence of genes of an organism.
• Genomics is the study of entire genomes(structure, function,
evolution, mapping, and editing of genomes)
• Executing the sequencing and analysis of entire human genome
enables more rapid and effective identification of disease associated
genes and provide drug companies with pre validated targets.
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3. Structural genomics:
• It is used to describe 3-D structure of every protein encoded by a
given genome.
• It has potential to inform knowledge of protein function.
• It characterize genome structures.
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Types of
Genomics
Structural
genomics
Functional
genomics

4. • Attempts to determine structure of every protein encoded by
genome rather than focusing on one particular protein.
• Various techniques used to determine structure of genome:
- De novo methods
-Sequence based Modeling
-Shortgun Sequencing
Functional genomics :
• Focus on gene transcription, translation, regulation of gene
expression and protein- protein interactions.
• Goal is to understand relationship between an organism genome and
its phenotype.
• Measure all gene products like mRNA or proteins within biological
sample.
Technique used :- DNA Microarray
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5. • Key areas of genomic study: Development and application of tools for
prediction and detection of
-genes
-sequence similarity
-motif/domain similarity
-gene expression variation ( measurement of mRNA levels
through microarray analysis : co expression, regulation etc)
• Gene expression analysis is been used extensively in the search for
new drug targets and for biomarkers of disease and therapeutic
activity.
• mRNA expression levels do not reliably predict protein expression
levels : limitation
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6. • Experimental note : Gene expression results can be quite different
from protein expression results, even when it is assayed on the same
sample under identical conditions.
- Half life, RNA and protein may have different half-lives in the
cell. RNA may get degraded before translation(by RNA
interference)
- Post translational modification: modifications occur after the
transcript has been translated into a protein.
-localization of protein : the site of activity of protein cannot be
predicted reliably from transcripts.
-Protein interactions: no info from transcripts on the interactions
with nucleotides, phospholipids, ligands or other proteins.
• These 4 are important for many biological functions, these limitations
illuminate the need to study the function, structure, and interactions
of the proteins themselves.
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7. • Proteins in a living organisms are The molecular targets of most drugs
on the market and in development.
• Study on proteins is a growing need for both basic science and in
drug discovery
• The study of function, structure and interaction of proteins at a wide
scale system lead to Proteomics .
• Proteomics has very close link to the genomics and metabolomics.
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8. Role of genomics
• The primary goal is to identify new molecular targets from genome.
• Process: identifying genes, profiling them, establishing a moderate
level of validation of their potential utility in addressing disease.
• Many elements of this process have been industrialized.
ex: Millennium pharmaceuticals industrialized gene to target
process; double output.
human genome sciences, GlaxoSmithKline – Genomic research
• Identification of additional gene family members and identification of
drug candidates that are much more selective for the target proteins.
• Many new targets for drug research and development , more the
targets better the choice of targets to work on ( choice is by using
knowledge and tools of genomics-understanding the molecular
pathway underlying disease)
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9. • Understanding the complete linkage of genes, transcription factors,
enzymes, receptors, modulators etc and their aberrations in disease
– better rational choice of the best target / pathway to intervene.
• Transcriptional profiling : Tool of genomics used to profile genes and
identify their association with disease. Over or under expression of
genes in a given situation provides information on molecular state.
• Various genomics technologies such as gene sequencing,
statistical genetics and gene expression analysis are used for the
drugs in clinical development and trials.
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11. Genome sequencing
• Gene number, exact locations, and functions & Gene regulation
• DNA sequence organization
• Chromosomal structure and organization
• Noncoding DNA types, amount, distribution, information content, and
functions and functions
• Coordination of gene expression, protein synthesis, and posttranslational
events translational events
• Interaction of proteins in complex molecular machines
• Predicted vs experimentally determined gene function
• Evolutionary conservation among organisms
• Protein conservation (structure and function)
• Correlation of SNPs (Single nucleotide polymorphisms ) with health and
disease
• Disease-susceptibility prediction based on gene sequence variation
• Genes involved in complex traits and multigene diseases
• Complex systems biology including microbial consortia useful for
environmental restoration environmental restoration
• Developmental genetics, genomics
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12. • Several genomics-based technologies already impact drug
development by contributing to the identification of new targets,
providing information for computer-aided design of lead compounds
and target validation through disease models and predictive
toxicology.
• By applying genomics technology, companies on average realize
savings of nearly US$300 million and two years per drug, largely as a
result of efficiency gains.
• This, ultimately helps in improved understanding of disease
mechanisms and the development of corresponding therapeutics.
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13. Proteomics
• Proteomics is the systematic high-throughput separation and
characterization of proteins within biological systems./ large scale
study of protein and their functions.
• Proteomics measures protein expression directly, not via gene
expression, thus achieving better accuracy. Current work uses 2-
dimensional polyacrylamide gel electrophoresis(2D- PAGE) and mass
spectrometry.
• New separation and characterization technologies, such as protein
microarray and high throughput chromatography are being
developed.
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14. Proteomic studies gives information includes
• Protein structure and function.
• Protein expression levels.
• Post translational modifications.
• Subcellular localization.
• Protein-protein interaction.
• Protein-nucleotide interaction.
• Protein lipid Interaction
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Process flowchart of Proteomics

16. • Proteomics can be applied as an assay procedure for the potential
utility of drug candidates.
• This can be achieved by a comparative analysis of reference protein
profiles from normal or diseased state with profiles after drug
treatment.
• This technology can also be integrated with combinatorial chemistry
to evaluate comparative SAR of drug analogues.
• Pharmaceutical proteomics for target validation split into
expression proteomics and cell mapping or interaction proteomics,
each having a distinct role in the overall drug discovery process.
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17. Functional areas of Proteomics
• Fractionation and purification: (Separation , isolation )
• Identification (Primary sequence) : determining primary amino acid
sequence of the proteins .
• Quantitation: How much of a protein has been detected.
• Characterization: Protein analysis and studies
-Sequence homologies
-Post translational modifications
-Functional analysis, including interactions, pathways and
networks
-Structural analysis and structure-function relationships.
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18. Fractionation and purification :
• Separation and purification of proteins.
• Low scale: Gel and column based fractionation, Differential
centrifugation. Centrifugation through bulk gradients.
• Proteins gets separated into bulk fractions/bands based on
size/charge.
• More advanced method: (Immunoprecipitation and affinity
chromatography) Individual protein from mixture.
• Most common separation methods for high throughput application
are 2D-PAGE , HPLC.
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19. 2D-PAGE (two dimensional polyacrylamide gel electrophoresis)
• Protein separation based on mass.
• Sample loaded onto a gel slab and an electric current is passed
through the gel, the current pulls the proteins down according to
their mass, separation by mass alone is not sufficient.
• Separation along first dimension of the gel by isoelectric point and
second dimension by mass.
• Results in a pattern of spots, each represents a protein of specific
mass and isoelectric point.
• Most effective and widely used.
• The results do not replicate well.
• Does not detect protein at low concentration.
• Proteins having similar mass appear at same spot.
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20. HPLC (High performance liquid chromatography)
• Column filled with packing material that separates proteins by eluting
them, detector at the end will identify the proteins.
• Gel filtration, ion exchange , affinity, hydrophobic interaction.
• This method is much faster , the results are more repeatable.
• More sensitive to low concentration proteins.
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21. Identification:
• Standard method: use the output of 2D PAGE directly : using
visualization tools, the gel can be read as to determine the mass and
iep of dark protein spots.
• Post translational modifications can change a proteins mass, thus
shifting the gel spot.
• It cannot identify an unknown protein.
• Proteins amino acid sequence must be determined
• Edman sequencing, mass spectrometry analysis(mass analyzers,
MALDI, Tandem mass spectroscopy, peptide mass fingerprinting)
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22. Quantitation
• To understand the relevance of given protein to a disease state.
• UV absorption at a wavelength of 280 is a very rapid, simple and
effective method of measuring a protein concentration in solution, its
accurate only when its extinction coefficient is known.
• Gel based methods can also be used.
• Staining techniques: coomassie blue staining, silver staining are
sensitive.
• MS will only measure the components that are present in the
mixture.
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23. Characterization:
• Protein sequence, structure, and function
• Proteins structure determines its function.
• A final 3 dimensional configuration of a protein, active sites and
binding sites determines the Protein’s biological or chemical function.
• Primary structure: Sequence of amino acids that forms the protein
chain. determines 3D configuration.
• Secondary structure: 3D structure of subsections of protein chain,
alpha helices, beta sheets
• Tertiary structure : alpha helices, beta sheets , and other secondary
structures assemble into a globular protein structure.
• Quaternary structure: individual protein chains further assemble into
dimers, trimers…etc
• Structures may not be complete at tertiary and quaternary stage,
PTM changes structures ,influence stability, function, interactions etc.
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24. Difference between Genomics and Proteomics
• The genome is relatively static.
• The proteome is not static; it changes constantly in response to tens of
thousands of intra- and extracellular environmental signals. The proteome varies
with various factors like health or disease, the nature of each tissue, the stage of
cell development, and effects of drug treatments.
• Genomics starts with the gene and makes inferences about its products
(proteins), whereas proteomics begins with the functionally modified protein
and works back to the gene responsible for its production.
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25. References
• Drug discovery and developemt, volume-1, Mukund S Chorghade.
• Smith and williams introduction to the principles of drug design and
action.
• Prakash N, Devangi P, (2010) Drug discovery, Journal of Antivirals and
antiretrovirals 2:063-068.doi:10.4172/jaa.1000025
• https://www.learner.org/courses/biology/textbook/proteo/proteo_1
4.html
• Use of genomics and proteomics in pharmaceutical drug discovery
and development: a review, sharma neha, harikumar s.L.
• https://www.slideshare.net/pallaviduggal2/role-of-target-
identification-and-target-validation-in-drug-discovery-
process?qid=21ad1fe1-4239-4eda-ac6e-
6d1926ae686e&v=&b=&from_search=1
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