Genomics Proteo Mics Based Drug Development and Process

Genomics & Proteomics Based Drug DISCOVERY
Dr. Basavaraj K. Nanjwade M.Pharm., Ph. D Associate Professor Department of Pharmaceutics KLE University BELGAUM 590010
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Dept.of Pharmaceutics
Genomics
Genetic scientist isolate individual genes and determine their chemical composition, and ultimately to sequence entire genomes. The sequencing of the human genome with the human genome project
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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 Coordination of gene expression, protein synthesis, and posttranslational events Interaction of proteins in complex molecular machines Predicted vs experimentally determined gene function
Dept.of Pharmaceutics 3
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Genome Sequencing

Evolutionary conservation among organisms Protein conservation (structure and function) Proteomes (total protein content and function) in organisms 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
Developmental genetics, genomics
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Genome Sequencing
C = Cytosine, G = Guanine, A = Adenine and T = Thymine

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Drug Discovery
SBI* can be used to examine:
drug targets (usually proteins) binding of ligands
rational drug design (benefits = saved time and RsRsRs)
* SBI-Structural Bioinformatics
Modern Drug Discovery

Whats different?
Drug
discovery process begins with a disease (rather than a treatment) disease model to pinpoint relevant genetic/biological components (i.e. possible drug targets)
Use
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disease genetic/biological target discovery of a lead molecule
- design assay to measure function of target - use assay to look for modulators of targets function
high throughput screen (HTS)

- to identify hits
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small molecule hits manipulate structure to increase potency *optimization of lead molecule into candidate drug*
fulfillment of required pharmacological properties:
potency, absorption, bioavailability, metabolism, safety
clinical trials
Interesting facts...
Over 90% of drugs entering clinical trials fail to make it to market The average cost to bring a new drug to market is estimated at $770 million
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Relating druggable targets to disease...

Analysis of Pharm industry reveals:
GPCR
Other 110 families
Over 400 proteins used as drug targets
STY kinases Cys proteases Gated ionchannel
Zinc peptidases Nuclear PDE receptor Serine proteases
Ion channels
P450 enzymes
Sequence analysis of these proteins shows that most targets fall within a few major gene families (GPCRs, kinases, proteases and peptidases)
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Assessing Target Druggability

Once
a target is defined for your disease of interest, SBI can help answer the question:
Is this a druggable target?

Does it have sequence/domains similar to known targets? Does the target have a site where a drug can bind, and with appropriate affinity?
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Genome Annotation and Analysis
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Impact of Structural Bioinformatics on Drug Discovery

Genome
Genomics Bioinformatics Structural Bioinformatics Chemoinformatics Structure-based Drug Design ADMET Modelling
Gene
Protein
HTS
Hit
Lead
Candidate Drug
. Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design
human genome
polysaccharides lipids
nucleic acids
proteins
Problems with toxicity, specificity, and difficulty in creating potent inhibitors eliminate the first 3 categories...
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human genome
polysaccharides lipids nucleic acids proteins
proteins with binding site
druggable genome = subset of genes which express proteins capable of binding small drug-like molecules
Proteomics
Proteomics studies networks of proteins by measuring, among other things, protein expression. Protein activity is regulated by post-translational modification and degradation; these cannot yet be predicted from DNA sequence. 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 microarrays and high-throughput chromatography, are being developed
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Proteomics
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Process Flow Chart of Proteomics

Two dimensional gel electrophoresis
(Image) analysis (Data massage, Evaluation)
Spot identification (Mass spectrometry)
Biomarkers (Principal compound analysis)

Proteomics in Drug Discovery
As we have seen genomics has dramatically altered the way drug discovery is now being viewed.
However, there may not be a good correlation between gene expression and protein expression as most disease processes and treatments are manifest at the protein level.
It is believed that gene-based expression analysis alone will be totally inadequate for drug discovery.
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Proteomics is Drug Discovery
Proteomics has unique and significant advantages as an important complement to a genomics approach. Target/marker identification
1.
2.
Target validation/toxicology
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Target/marker identification
This application of proteomics provides a protein profile of a cell, tissue and/or bodily fluids that can be used to compare a healthy with a diseased state for protein differences in the search for drugs or drug targets.
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Target validation/toxicology
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 states with profiles after drug treatment (Wang 1999). Proteomics technology can also be integrated with combinatorial chemistry to evaluate comparative structure-activity relationships of drug analogs.
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Protein-Ligand Docking
Starting orientation of the program with 2 water molecules as the Protein and Ligand (a useful setup for testing the application). The energy of the system is in J/mol.
Independent control of both molecules is allowed. The leftmost molecule is rotated using a trackball style rotation, while the second molecule remains fixed.
From the previous figure, the second molecule has been independently translated up and away from the first molecule. Molecules can be arbitrarily positioned and oriented in 3D
This is the same setup as the previous figure, except the viewpoint has been rotated, translated and zoomed to a different location. The energy of the system remains the same as the molecules are physically unmoved relative to each other
The two oxygen atoms are just overlapping and consequently the energy of the system takes on a large negative value indicating a VERY high energy (the energy well is reversed for the purpose of the program, so large positive values indicate a favourable conformation, and large negative values indicate unfavourable conformations
Here the atoms are at an optimum distance for the van der Waals Forces to hit the minimum of the well potential. However, the atoms are not aligned for any dipole-dipole interaction or hydrogen bonding
The energy of the system attains a maximum with the following orientation. This is the orientation that occurs between water molecules when ice forms. This puts the hydrogen bond in its optimum orientation, and this changes makes another order of magnitude difference in the energy of the system
Structure being the key to function, determining a proteins structure is a key step toward elucidating its role. The subfield of protein-ligand docking is useful in rational drug design. Laboratory prediction is time consuming and expensive, so researchers have been working on computerized prediction for several decades. Exact computational prediction is difficult but sophisticated algorithms to find approximate solutions continue to be developed.
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Critical Assessment of Methods of Protein Structure Prediction

Computational groups predict structures of proteins whose structures have been found in the laboratory before the latter results are released. Tools are Classified
1.
Comparative modeling looks for amino acid similarity to proteins of known structure.
2.
Fold recognition predicts folds in regions that do not share amino acid similarity with known structures
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Advantages

More Powerful Medicines Better, Safer Drugs the First Time More Accurate Methods of Determining Appropriate Drug Dosages Advanced Screening for Disease Better Vaccines Improvements in the Drug Discovery and Approval Process Decrease in the Overall Cost of Health Care
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Disadvantages
Complexity of finding gene variations that affect drug response Limited drug alternatives Disincentives for drug companies to make multiple pharmacogenomic products Educating healthcare providers
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THANK YOU
E-mail: bknanjwade@yahoo.co.in
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Genomics Proteo Mics Based Drug Development and Process

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Genomics Proteo Mics Based Drug Development and Process

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Genomics & Proteomics Based Drug DISCOVERY

C = Cytosine, G = Guanine, A = Adenine and T = Thymine

Modern Drug Discovery

Modern Drug Discovery

high throughput screen (HTS)

Modern Drug Discovery

Relating druggable targets to disease...

Other 110 families

Over 400 proteins used as drug targets

STY kinases Cys proteases Gated ionchannel

Zinc peptidases Nuclear PDE receptor Serine proteases

Assessing Target Druggability

Is this a druggable target?

Genome Annotation and Analysis

Impact of Structural Bioinformatics on Drug Discovery

proteins with binding site

Process Flow Chart of Proteomics

(Image) analysis (Data massage, Evaluation)

Spot identification (Mass spectrometry)

Biomarkers (Principal compound analysis)

Proteomics in Drug Discovery

Proteomics is Drug Discovery

Critical Assessment of Methods of Protein Structure Prediction

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