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DRUG DESIGNINGPresented By: Paarsa Hassan Zainab Nooruddin

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INTRODUCTION

• Chemical or biological substances.• Single compounds or a mixture of different

compounds.• In the past, treatment through traditional remedies.• Present day, diseases are cured on molecular levels.

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HISTORY

– Plants or Natural Product• Plant and Natural products were source for

medical substance• Example: foxglove used to treat congestive heart

failure– Accidental Observations• 1928: Alexander Fleming observed the effect of

mold• Mold (Penicillium) produce substance penicillin

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DRUG TARGETS

• Target Molecular recognition site to which drug binds• Target may be

– Protein molecule A receptor Enzyme Transport molecule Ion channel Tubulin Immunophilin

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TYPES

There are four different methodologies commonly used in the drug designing:1) Ligand-Based Drug Design or Indirect Drug

Design2) Structure-Based Drug Design or Direct Drug

Design3) Rational Drug Design4) Computer-Assisted Drug Design

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Mechanism Based Drug Design• When the disease process is understood at the

molecular level and the target molecule(s) are defined

• Drugs can be designed specifically to interact with the target molecule in such a way as to disrupt the disease.

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Structure-Based Drug Design• First techniques to be used in drug design.• Helped in the discovery process of new drugs.• Information about the structural dynamics and

electronic properties about ligands are obtained from calculations.

• Structure-based drug design can be divided roughly into two categories:

I. Ligand basedII. Receptor Based

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• The first category is about “finding” ligands for a given receptor.

• A large number of potential ligand molecules are screened

• This method is usually referred as ligand-based drug design.

• It saves synthetic effort to obtain new lead compounds.

Ligand-Based Drug Design

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W h a t i s D o c k i n g ?

• Docking attempts to find the “best” matching between two molecules• It includes finding the Right Key for the Lock • Given two biological molecules determine:

- Whether the two molecules “interact”- If so, what is the orientation that maximizes the “interaction”

while minimizing the total “energy” of the complex

Goal: To be able to search a database of molecular structures and retrieve all molecules that can interact with the query

structure

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Receptor Based Drug Design

• Another category is about “building” ligands, which is usually referred as receptor-based drug design.

• Ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner.

• These pieces can be either individual atoms or molecular fragments.

• The key advantage of such a method is that novel structures, not contained in any database, can be suggested.

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Computer Aided Design

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Techniques of Drug Design

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• Starting point for gathering information from mechanistic drug design.

• Determine structural information about a molecule.• Provides the critically important coordinates needed

for the handling of data by computer modeling system.

X-Ray Crystallography

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Nuclear Magnetic Resonance (NMR)

• NMR uses much softer radiation • Examine molecules in the more mobile liquid phase• Three-dimensional information will be obtained.• Examines small molecule-macromolecule

complexes.

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Homology Modeling• Homology modeling, also known as comparative

modeling of protein.• Constructing an atomic-resolution model of the

"target" and an experimental three-dimensional structure of a related homologous protein.

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Computer Aided Drug Design

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HOW IS A DRUG DEVELOPED?• The development of a new therapeutic drug is a:I. ComplexII. LengthyIII. Expensive• It can take 10-15 years• Over $500 million to develop a drug from an

initial concept.

Identify Disease

Isolate Protein(2-5 years)

Find a Drug (2-5 years)

Preclinical testing(1-3 years)

Human clinical trials(2-10 years)

FDA approval(2-3 years)

File

IN

D

File

NDA

Identify Disease

Isolate ProteinFinding Drug

Preclinical Testing

TARGET SELECTION

LEAD DISCOVERY

MOLECULAR MODELING

VIRTUAL SCREENING

COMBINATORIAL CHEMISTRY

IN VITRO & IN SILICO ADME MODELS

Cellular & Genetic Targets

High Throughput Screening

In-silico Screening

Chemical Synthesis

Computer graphics & models help improve activity

Tissue and computer models begin to replace animal testingFi

le

IND

Human Clinical Trials File

NDA

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CONCLUSION

Drug Designing is a multidisciplinary, complex, costly and intellect intensive process.

Modern drug design techniques can make drug discovery process more fruitful & rational.

Knowledge management and technique specific expertise can save time & cost, which is a paramount need of the hour.

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REFERENCES

• http://www.yourgenome.org/facts/how-are-drugs-designed-and-developed

• http://rxcinternational.com/different-types• http://slideplayer.com/slide/10688957/

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THANK YOU

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