drug designing- jaideep sarkar

8/3/2019 Drug Designing- JAIDEEP SARKAR

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Drug Design(DOCKING)

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P

By:

JAIDEEP SARKAR


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High Throughput Screeningp104 ligands per day

Drug Des ign

But: Hit Rate 10-6 per ligand


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RATIONAL DRUG D E S I GN

Compound

databases,

Microbial broths,

Plants extracts,

Combinatorial

Libraries

3-D ligand

Databases

Docking

Linking or

Binding

Receptor-Ligand

Complex

Random

screening

synthesis

Lead molecule

3-D QSAR

Target Enzyme

OR Receptor

3-D structure by

Crystallography,NMR, electron

microscopy OR

Homology Modeling

Redesign

to improve

affinity,

specificity etc.

Testing


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Structure specific drugs

Act at specific sites (receptor or enzyme)-Activity/potency susceptible to small changes in

structure

Ex.- It took Pfizer about 18 years to develop the anti-inflammatory drug Piroxicam, which

was launched in 1980 during the golden age of rational drug discovery

MECHANISM OF DRUGACTION


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Substrate

Protein

Ligand

BINDING

REACTION

FUNCTION

STRUCTURAL

CHANGE


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What is Docking?

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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The Process

Identify disease

protein Identify active siteDetermine structure

of Protein

Virtual Screening of

Drug Candidates

Synthesis of Lead

Compounds

Pharmacological

Testing

Optimisation Clinical Trials Drug


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D o c k i n g P r o t o c o l


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c o n t d . . .

RANDOM START POSITION:

Creation of a decoy begins with a random orientation of

each partner and a translation of one partner along the line

of protein centers to create a glancing contact between the

proteins


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Lead Op t imiza t ion

Lead Lead OptimizationActive site

Express proteins

with changes in

amino acid

sequences

Identify amino

acids involved infunction


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Generate molecular surface of protein

Cavities in the receptor are used to

define spheres (blue); the centres

are potential locations for ligand atoms.

Sphere centres are matched to ligand

atoms, to determine possible orientations

for the ligand. 104 orientations generated

How DOCK works.


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Virtual screening, toidentify potential leadcompounds from a large

dataset Known structures of organic

compounds

Libraries of Virtual Compounds

Programs calculate affinity forprotein

Narrow down to small number of

possiblities

Surfacerepresentation thatefficiently represents the docking

surface and identifies the regions of

interest (cavities and protrusions)

Surface matching that matches

surfaces to optimize a binding score


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Poseprediction

If we know exactly

where and how aknown ligand binds...

We can see which

parts are importantfor binding

We can suggest

changes to improve

affinity

Avoid changes that

will clash with the

protein


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Monte Carlo methods (MC)

Molecular Dynamics (MD)

Simulated Annealing (SA)

Genetic Algorithms (GA)

Available in packages:

Auto Dock (MC,GA,SA)

GOLD (GA)

Sybyl (MD)

Rosetta DOCK (Baker ,

Washington Univ., Gray,

Johns Hopkins Univ.)

Introducing flexibility:

Whole molecule docking programs

Glide (Schrodinger)


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Why is docking important?

It is the key to rational drug design: The results of

docking can be used to find inhibitors for specific

target proteins and thus to design new drugs. It isgaining importance as the number of proteins

whose structure is known increases

In addition to new drug discovery, it is of extreme

relevance in cellular biology, where function isaccomplished by proteins interacting with

themselves and with other molecular components


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M o d i f i e d Simple A l g o r i t h m a n d 3D

Superposi t ion and A l ignment


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Drug Discovery by Drug Designing

Case Study: Tuberculosis

Crystals &

Crystal structure

Lead compound

Virtual Screening

Combinatorial chemistryEnzyme assay

-0.006 -0.004 -0.002 0 0.002 0.004 0.006 0.008 0.010 0.012 0.014-1

0

1

2

3

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5

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7AccD5-NCI65828

1/[Malonyl-CoA]um-1

1/Vo(min-1

)

[I] = 0.00

[I] = 2.50

[I] = 5.00

[I] =10.00

TB ACCase,AccD5


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Docking

The Computational Loop -

Similarity Search


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Structure-Based Drug Design

Identified AccD5 Inhibitors

New TB drug lead

HO3S

NH2

N

N

OH


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Why i s th i s d i f f i cu l t? Both molecules are flexible and may alter each others

structure as they interact:

Hundreds to thousands of degrees of freedom (DOF)

Total possible conformations are astronomical


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Trypsinogen

Trypsin

Chymotrypsinogen

Chymotrypsin

Duodenal Cell

Enterokinase


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USES OF DOCKING

Drug targets Protein- ligand interactions that otherwise may be

overlooked

Better understand the Machinery ofLife

Enzyme-inhibitor class

Antibody-antigen class

Others

Protein Therapies

Engineered Protein Enzymes Although the reliability of docking methods is not so

high, they can provide new suggestions

False positives rates can be reduced using several scoring

functions in a consensus-scoring strategy


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Large tomatoes can evolve from wild,blueberry-size tomatoes. The genetic

mechanism responsible for this is

similar to the one that proliferates

cancer cells in mammalians. That's a

connection nobody could have made

in the past.

Cancer cell growth appears to be related to

evolutionary development of plump fruits and

vegetables

ADVANCE USE.


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Future Challenges For Docking

Better Scoring Functions

High-Throughput Screening

Tractable Models ofFlexibility

The so-called computational molecular docking problem is farfrom being solved. There are two major bottle-necks:

1. The algorithms can handle only a limited extent of

backbone flexibility2. The availability of selective and efficient scoring

functions


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drug designing- jaideep sarkar

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