Computer Aided Drug Design (Cadd) : Naresh.T M.Pharmacy 1 YR/1 SEM

COMPUTER
AIDED
DRUG DESIGN(CADD)
NARESH.T
M.PHARMACY 1ST YR/1ST SEM
DRUG DESIGN
It is the inventive process of finding new

medications based on the knowledge of a biological target.
The drug is most commonly an organic small molecule that

activates or inhibits the function of a biomolecule such as
a protein, which in turn results in a therapeutic benefit to
the patient.
In the most basic sense, drug design involves the design of

small molecules that are complementary in shape and charge
to the biomolecular target with which they interact and
therefore will bind to it.
TERMS TO BE KNOWN
MOLECULAR
PHARMACOPH
MOLECULAR
LIGAND
DOCKING
PHARMACOPH
ORE
LIGAND
DOCKING
ORE
L
E
A
D
I
D
E
N
T
I
F
I
C
A
T
I
O
N
Drug Discovery & Development
Identify disease
Find a drug effective
against disease protein
(2-5 years)
Isolate protein
involved in
disease (2-5 years)
Preclinical testing
Human clinical trials
(1-3 years)
D
(2-10 years)
IN
Formulation &
le
Fi
Scale-up
A
ND
le
Fi
FDA approval
(2-3 years)
modern drug discovery process
Target Target Lead Lead Preclinical Drug

identification validation identification optimization phase discovery
6-9 years
2-5 years
• Drug discovery is an expensive process involving high R & D cost and extensive
clinical testing.
• A typical development time is estimated to be 10-15 years.
Design, development and commercialization of a
drug is a tedious, time-consuming and cost-intensive process
Timeline in a drug discovery project.

INTRODUCTION
Medicinal chemists today are facing a serious challenge because of the
increased cost and enormous amount of time taken to discover a new drug,
and also because of fierce competition amongst different drug companies.
It needs approximately 300 to 350 million US $ and 12-13 years

for a drug to reach the market.
Considering both the potential benefits to human health and the enormous
costs in time and money of drug discovery.
technique that increases the efficiency of any stage of the drug

discovery enterprise will be highly prized.
Computer-aided drug design (CADD) is one of these tools which can be used
to increase the efficiency of the drug discovery process. CADD cannot, however,
maximize its utility in isolation and will not do so. Rather, it can form a
valuable partnership with experiment by providing estimates when experiments
are difficult, expensive, or impossible, and by coordinating the experimental data
available.
A close coupling between computational chemists and experimentalists allows

information to flow immediately and directly between the two. This helps CADD
chemists to better understand the details of the problem and to refine their
approach. It also provides valuable information for the experimentalist, it helps
to guide further experimental planning and potentially makes this process more
efficient
CADD is, however, not a direct route to new drugs, but it provides a somewhat
more detailed map to the goal. The hope is that by providing bit and pieces of
information, and by helping to coordinate the information, CADD will help to
save days and money for drug discovery projects
Traditional Drug Screening
• Random, trial and error

• Time consuming
• Very expensive
• Extremely low yield ( 1 in 100,000)
Computer-based Design
• Target specific and structure-based

• Fast and automatic
• Very low cost
• High success rate
L S
O
T

O
Identify target disease

C



Study Interesting Compounds
Detection the Molecular Bases for Disease
Rational Drug Design Techniques
A
D
 Refinement of Compounds
 Quantitative Structure Activity Relationships (QSAR)
 Solubility of Molecule
 Drug Testing
D
Identify Target Disease
know all about the disease
A real drug needs to be developed
drug must influence the target protein
INSILICO methods
Study Interesting Compounds
1.One needs to identify and study the lead

compounds that have some activity against a disease.
2. These compounds provide a starting point for refinement of the chemical

structures.
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.
Detect the Molecular Bases for Disease
1. Traditionally, the primary way of determining what compounds

would be tested computationally was provided by the researchers'
understanding of molecular interactions.
2. A second method is the brute force testing of large numbers of

compounds from a database of available structures.
database known actives structures found

Rational drug design techniques:-
1.These techniques attempt to reproduce the researchers' understanding

of how to choose likely compounds built into a software package that is
capable of modeling a very large number of compounds in an automated
way.
2. Many different algorithms have been used for this type of testing,
many of which were adapted from artificial intelligence applications.
3.The complexity of biological systems makes it very difficult to

determine the structures of large biomolecules.
4. Ideally experimentally determined (x-ray or NMR) structure is

desired, but biomolecules are very difficult to crystallize
Refinement of compounds
Once you got a number of lead compounds have been found,

computational and laboratory techniques have been very successful in
refining the molecular structures to give a greater drug activity and
fewer side effects.
Done both in the laboratory and computationally by examining the

molecular structures to determine which aspects are responsible for
both the drug activity and the side effects.
Quantitative Structure Activity Relationships
(QSAR):-
1.Computational technique should be used to detect the functional

group in your compound in order to refine your drug.
2. QSAR consists of computing every possible number that can
describe a molecule then doing an enormous curve fit to find out
which aspects of the molecule correlate well with the drug activity or
side effect severity.
3. This information can then be used to suggest new chemical
modifications for synthesis and testing
Solubility of Molecule:-
1. One need to check whether the target molecule is water soluble or
readily soluble in fatty tissue will affect what part of the body it
becomes concentrated in.
2. The ability to get a drug to the correct part of the body is an

important factor in its potency.
3. Ideally there is a continual exchange of information between the

researchers doing QSAR studies, synthesis and testing.
4. These techniques are frequently used and often very successful since
they do not rely on knowing the biological basis of the disease which can
be very difficult to determine.
Drug Testing
1. Once a drug has been shown to be effective by an initial assay

technique, much more testing must be done before it can be given to
human patients.
2. Animal testing is the primary type of testing at this stage. Eventually,

the compounds, which are deemed suitable at this stage, are sent on to
clinical trials.
3. In the clinical trials, additional side effects may be found and human
dosages are determined.
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and “personalized” targets
HIGH THROUGHPUT SCREENING

Identify disease Screening up to 100,000 compounds a
day for activity against a target protein
VIRTUAL SCREENING
Using a computer to
Isolate protein predict activity
COMBINATORIAL CHEMISTRY
Rapidly producing vast numbers Find drug
of compounds
MOLECULAR MODELING
Computer graphics & models help improve activity
Preclinical testing
IN VITRO & IN SILICO ADME MODELS
Tissue and computer models begin to replace animal testing
Impact of new technology on drug discovery
• The last few years have seen a number of

“revolutionary” new technologies:
– Gene chips, genomics.
– Bioinformatics & Molecular biology
– protein structures
– High-throughput screening & assays
– Docking
– Combinatorial chemistry
– In-vitro ADME testing
• How do we make it all work for us?

Information generated at different points in the Drug Design process
Gene chip experiments

Protein structures
Project selection decisions
Assay protocols
Series selection decisions
SAR studies
Combinatorial Expts.
Pharmacophores
ADME studies
Lead cmpd decisions
Toxicology studies
D
IN
Scaleup reactions
le
Fi
A
ND
Clinical Trials data
le
Fi
Doctor/patient studies
Marketing, surveys, etc

Software for General Purpose Molecular Modeling
For workstations, minicomputers, and supercomputers (SGI, Sun,

Cray, etc.)
AMBER — Peter Kollman and coworkers, UCSF
Computer assisted model building, energy minimization,
molecular dynamics, and free energy perturbation calculations.
Midas Plus — UCSF Computer Graphics Laboratory
CHARMM — Martin Karplus and cowrokers, Harvard
QUANTA/CHARMm — Molecular Simulations Inc. (MSI)
molecular/drug design, QSAR, quantum chemistry,
X-ray & NMR data analysis
Insight/DISCOVER — Biosym, Inc.
Now MSI and Biosym became Accelrys Inc.
SYBYL — Tripos, Inc.
ECEPP — (Harold Scheraga and coworkers, Cornell)
MM3 — (Norman Allinger and coworkers, Georgia)
Molecular docking
Ligand Docking into a Protein Binding Site
Assignment of Interaction Sites
A Perfect Ligand
Rigid Docking (e.g. LUDI)
Multiple Conformations / Flexible Docking
Linking (e.g. LUDI, SAR by NMR)
Computer-Aided Drug
Design
Different Strategies
GRID Analysis of the Thrombin Binding Site
Terms Contributing to Ligand Binding
π interactions
hydrogen bonds
(directed interactions
hydrophobic ligand and protein

contacts flexibility
explicitly placed
water molecules
rt
C
ha
wc
Flo
A
D
D
I
N
S
I
C
A
L
I
C
O
M
E
T
D
H
O
D
D
Pharmaceutical Research Software
Spartan is a powerful tool for computer aided drug design. The easy-
to-use interface delivers a new suite of molecular modelling features
as well as quantum calculation tools for chemists working in drug
discovery.
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
PHARMACO informatics 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
THANK
YOU

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COMPUTER

It is the inventive process of finding new

The drug is most commonly an organic small molecule that

In the most basic sense, drug design involves the design of

Target Target Lead Lead Preclinical Drug

Timeline in a drug discovery project.

It needs approximately 300 to 350 million US $ and 12-13 years

technique that increases the efficiency of any stage of the drug

A close coupling between computational chemists and experimentalists allows

• Random, trial and error

• Target specific and structure-based

Identify target disease

know all about the disease

A real drug needs to be developed

drug must influence the target protein

1.One needs to identify and study the lead

2. These compounds provide a starting point for refinement of the chemical

4. Lead optimization tools such as WABE offer a rational approach to drug

1. Traditionally, the primary way of determining what compounds

2. A second method is the brute force testing of large numbers of

database known actives structures found

1.These techniques attempt to reproduce the researchers' understanding

3.The complexity of biological systems makes it very difficult to

4. Ideally experimentally determined (x-ray or NMR) structure is

Once you got a number of lead compounds have been found,

Done both in the laboratory and computationally by examining the

1.Computational technique should be used to detect the functional

2. The ability to get a drug to the correct part of the body is an

3. Ideally there is a continual exchange of information between the

1. Once a drug has been shown to be effective by an initial assay

2. Animal testing is the primary type of testing at this stage. Eventually,

HIGH THROUGHPUT SCREENING

• The last few years have seen a number of

• How do we make it all work for us?

Gene chip experiments

Marketing, surveys, etc

For workstations, minicomputers, and supercomputers (SGI, Sun,

hydrophobic ligand and protein

1. SVMProt: Protein function prediction software

2. INVDOCK: Drug target prediction software

3. MoViES: Molecular vibrations evaluation server

2. Drug adverse reaction target database

3. Drug ADME associated protein database

4. Kinetic data of biomolecular interactions database

5. Computed ligand binding energy database

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