Application of Bioinformatics in

various fields

Ravi Kapopara
General Application
Application in Drug Discovery
Molecular medicine
 The completion of the human genome means that we can
search for the genes directly associated with different
diseases and begin to understand the molecular basis of
these diseases more clearly.
 This new knowledge of the molecular mechanisms of
disease will enable better treatments, cures and even
preventative tests to be developed.
Personalized medicine
Today, doctors have to use trial and error to find the
best drug to treat a particular patient as those with the
same clinical symptoms can show a wide range of
responses to the same treatment.
In the future, doctors will be able to analyse a patient's
genetic profile and prescribe the best available drug
therapy and dosage from the beginning.
Preventative medicine
With the specific details of the genetic mechanisms of
diseases being unravelled, the development of
diagnostic tests to measure a persons susceptibility to
different diseases may become a distinct reality.
Preventative actions such as change of lifestyle or
having treatment at the earliest possible stages when
they are more likely to be successful, could result in
huge advances in our struggle to conquer disease.
Gene therapy
In the not too distant future, the potential for using
genes themselves to treat disease may become a
reality.
Gene therapy is the approach used to treat, cure or
even prevent disease by changing the expression of
person’s genes.
Currently, this field is in its infantile stage with clinical
trials for many different types of cancer and other
diseases ongoing.
Drug development
At present all drugs on the market target only about
500 proteins.
With an improved understanding of disease
mechanisms and using computational tools to identify
and validate new drug targets, more specific medicines
that act on the cause, not merely the symptoms, of the
disease can be developed.
These highly specific drugs promise to have fewer side
effects than many of today's medicines.
Microbial genome applications
By studying the genetic material of these organisms,
scientists can begin to understand these microbes at a
very fundamental level and isolate the genes that give
them their unique abilities to survive under extreme
conditions.
General Application
Climate change Studies
Alternative energy sources
Biotechnology
Antibiotic resistance
Forensic analysis of microbes
Evolutionary studies
Crop improvement
Insect resistance
Improve nutritional quality
Vetinary Science
Comparative Studies
APPLICATIONS OF BIOINFORMATICS IN DRUG
DISCOVERY
 Bioinformatics Tools
The processes of designing a new drug using bioinformatics tools have open a new
area of research. However, computational techniques assist one in searching
drug target and in designing drug in silco, but it takes long time and money. In
order to design a new drug one need to follow the following path.
Identify target disease
Study Interesting Compounds
Detection the Molecular Bases for Disease
Rational Drug Design Techniques
Refinement of Compounds
Quantitative Structure Activity Relationships (QSAR)
Solubility of Molecule
Drug Testing
Genomics
Database Description

GOLD (http://wit.integratedgenomics.com/GOLD/) Genomes online database, provides large and detailed

TIGR microbial Database
(http://www.tigr.org/tdb/mdb/mdbcomplete.html)
monitoring of genome sequencing project. According
to it there are about 110 completely sequenced
genomes.
Listing of published microbial genomes and
chromosomes and those in progress.

EBI complete Genomes Gives the data on completed Genomes

(http://www.ebi.ac.uk/genomes/)

NCBI Genomic Biology Keeps a wide range of data on genomes

(http://www.ncbi.nlm.nih.gov/Genomes/)

National Human Genome Research Institute Home of an international research effort to determine
(http://www.genome.gov) the DNA sequence of entire Genome. Contributes to
the Human Genome Project include the National
Institute of Health (NIH).
Bioinformatics tools for Genomics
analysis
SLAM : Gene finding, alignment, annotation (human-
mouse homology identification)
ACT (Artemis Comparison Tool) : comparative
genomics
Gene Finder (Tool for finding out the gene from
protein or nucleotide sequences)
Proteomics

“Systematic analysis of protein profiles of tissues”

Bigger field than genomics.
Types of Proteomics
Structural Proteomics
Functional Proteomics
Cell map proteomics
Expression Proteomics
Structural Proteomics
Goals to map out the 3-D structures of proteins and
protein complexes
Provides Structural framework for understanding
execution of protein’s function
Different protein = different structure domains +
different function
RasMol (A tool for Protein 3D structure prediction)
Functional Proteomics
To find out the role of protein in cellular process
Depending on their cellular location , cell types where
they are expressed , multimeric state and bound
substarte
Arraying functional proteins on a chip is the technique
to find out it’s function
Cell map proteomics
Determination of subcellular location of proteins and
PPI (Protein -Protein Interaction) by purification of
protein complexes followed by MS (Mass
Spectrometric) identification.
Yeast two-hybrid method is used to find PPI
GRAMM is online server to find out PPI
Expression Proteomics
Creation of quantitative maps of expressed proteins
from cell or tissue extracts
Protein Separation by 2-D Gel Electrophoresis
Identify by MS
Function of Proteomics
• Uses information determined by biochemical/crystal structure
methods
• Visualization of protein structure (RasMol)
• Make protein-protein comparisons (GRAMM)
• Used to determine:
 conformation/folding
 antibody binding sites
 protein-protein interactions
 computer aided drug design
Bioinformatics tools for Proteomics
analysis
 PepMAPPER, PeptideSearch = PMF tool

 ProFound = A tool for searching a protein sequence

database using information from mass spectra of peptide
maps
 PAWS = A tool for analysis of protein sequence and post
translation modification
 ExPasy is the main database which contain so many tools
for protein identification and charecterization
Computer-Aided Drug Design
(CADD)
 Computer-Aided Drug Design (CADD) is a specialized
discipline that uses computational methods to simulate
drug-receptor interactions.

 CADD methods are heavily dependent on bioinformatics

tools, applications and databases. As such, there is
considerable overlap in CADD research and
bioinformatics.
 Bioinformatics Supports CADD
Research 
Virtual High-Throughput Screening (vHTS):-

1. Pharmaceutical companies are always searching for new leads

to develop into drug compounds.

2. One search method is virtual high-throughput screening. In

vHTS, protein targets are screened against databases of small-
molecule compounds to see which molecules bind strongly to
the target.
 Bioinformatics Supports CADD Research
 Virtual High-Throughput Screening (vHTS):-

3. If there is a “hit” with a particular compound, it can be

extracted from the database for further testing.

4. With today’s computational resources, several million

compounds can be screened in a few days on sufficiently large
clustered computers.

5. Pursuing a handful of promising leads for further development

can save researchers considerable time and expense.
e.g.. ZINC is a good example of a vHTS compound library.
 Bioinformatics Supports CADD Research
 Sequence Analysis: -

1. In CADD research, one often knows the genetic sequence of multiple

organisms or the amino acid sequence of proteins from several species.

2. It is very useful to determine how similar or dissimilar the organisms are

based on gene or protein sequences.

3. With this information one can infer the evolutionary relationships of the
organisms, search for similar sequences in bioinformatic databases and
find related species to those under investigation.

4. There are many bioinformatic sequence analysis tools that can be used
to determine the level of sequence similarity. 
 Bioinformatics Supports CADD Research
 Homology Modeling:-

1. Another common challenge in CADD research is determining the 3-

D structure of proteins.

2. Most drug targets are proteins, so it’s important to know their 3-D
structure in detail. It’s estimated that the human body has 500,000 to
1 million proteins.

3. However, the 3-D structure is known for only a small fraction of

these. Homology modeling is one method used to predict 3-D
structure.
 Bioinformatics Supports CADD Research
 Homology Modeling:-

4. In homology modeling, the amino acid sequence of a specific

protein (target) is known, and the 3-D structures of proteins
related to the target (templates) are known.

5. Bioinformatics software tools are then used to predict the 3-D

structure of the target based on the known 3-D structures of the
templates. 

6. MODELLER is a well-known tool in homology modeling, and

the SWISS-MODEL Repository is a database of protein
structures created with homology modeling.
 Bioinformatics
Similarity Supports CADD Research
Searches:-

1. A common activity in biopharmaceutical companies is the

search for drug analogues.

2. Starting with a promising drug molecule, one can search for

chemical compounds with similar structure or properties to a
known compound.

3. There are a variety of methods used in these searches, including

sequence similarity, 2D and 3D shape similarity, substructure
similarity, electrostatic similarity and others.

4. A variety of bioinformatic tools and search engines are

available for this work
Bioinformatics Supports CADD Research
 Drug Lead Optimization:-

1. When a promising lead candidate has been found in a drug

discovery program, the next step (a very long and
expensive step!) is to optimize the structure and properties
of the potential drug.

2. This usually involves a series of modifications to the

primary structure (scaffold) and secondary structure
(moieties) of the compound.
 Bioinformatics Supports CADD Research
Drug Lead Optimization:-

3. This process can be enhanced using software tools

that explore related compounds (bioisosteres) to the
lead candidate. OpenEye’s WABE is one such tool.

4. Lead optimization tools such as WABE offer a

rational approach to drug design that can reduce the
time and expense of searching for related compounds.
 Bioinformatics Supports CADD Research
 Physicochemical Modeling:-

1. Drug-receptor interactions occur on atomic scales.

2. To form a deep understanding of how and why drug

compounds bind to protein targets, we must consider
the biochemical and biophysical properties of both the
drug itself and its target at an atomic level.

3. Swiss-PDB is an excellent tool for doing this. Swiss-PDB

can predict key physicochemical properties, such as
hydrophobicity and polarity that have a profound
influence on how drugs bind to proteins.
 Bioinformatics Supports CADD Research
 Drug Bioavailability and Bioactivity:-

1. Most drug candidates fail in Phase III clinical trials after many
years of research and millions of dollars have been spent on
them. And most fail because of toxicity or problems with
metabolism.

2. The key characteristics for drugs are Absorption, Distribution,

Metabolism, Excretion, Toxicity (ADMET) and efficacy—in
other words bioavailability and bioactivity.

3. Although these properties are usually measured in the lab, they

can also be predicted in advance with bioinformatics
software.       
Benefits of CADD
Cost Savings:-

1. The Tufts Report suggests that the cost of drug

discovery and development has reached $800
million for each drug successfully brought to
market.

2. Many biopharmaceutical companies now use

computational methods and bioinformatics tools to
reduce this cost burden.
 Benefits of CADD
Cost Savings:-

3. Virtual screening, lead optimization and predictions

of bioavailability and bioactivity can help guide
experimental research.

4. Only the most promising experimental lines of

inquiry can be followed and experimental dead-ends
can be avoided early based on the results of CADD
simulations.
Benefits of CADD

Time-to-Market:-

1. The predictive power of CADD can help drug

research programs choose only the most promising
drug candidates.

2. By focusing drug research on specific lead

candidates and avoiding potential “dead-end”
compounds, biopharmaceutical companies can get
drugs to market more quickly. 
Benefits of CADD
Insight:-

1. One of the non-quantifiable benefits of CADD

and the use of bioinformatics tools is the deep
insight that researchers acquire about drug-receptor
interactions.

2. Molecular models of drug compounds can reveal

intricate, atomic scale binding properties that are
difficult to envision in any other way.
 Benefits of CADD
Insight:-

1. When we show researchers new molecular models of

their putative drug compounds, their protein targets
and how the two bind together, they often come up
with new ideas on how to modify the drug compounds
for improved fit.

2. This is an intangible benefit that can help design

research programs.
CADD
 CADD and bioinformatics together are a powerful
combination in drug research and development.

An important challenge for us going forward is finding

skilled, experienced people to manage all the
bioinformatics tools available to us, which will be a
topic for a future article.
Research Achievements
Software developed

Bioinformatics data base developed

 Software developed
1. SVMProt: Protein function prediction software
http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi

2. INVDOCK: Drug target prediction software

3. MoViES: Molecular vibrations evaluation server

http://ang.cz3.nus.edu.sg/cgi-bin/prog/norm.pl
 Bioinformatics database developed
1. Therapeutic target database
http://xin.cz3.nus.edu.sg/group/cjttd/ttd.asp
2. Drug adverse reaction target database
http://xin.cz3.nus.edu.sg/group/drt/dart.asp
3. Drug ADME associated protein database
http://xin.cz3.nus.edu.sg/group/admeap/admeap.asp
4. Kinetic data of biomolecular interactions database
http://xin.cz3.nus.edu.sg/group/kdbi.asp
5. Computed ligand binding energy database
http://xin.cz3.nus.edu.sg/group/CLiBE/CLiBE.asp