Computer aided Drug designing (CADD)

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Drug Design(DOCKING)

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By: JAIDEEP SARKAR

High Throughput Screening104 ligands per day

Drug Design

But: Hit Rate 10-6 per ligand

RATIONAL DRUG DESIGN

Compound databases,

Microbial broths,Plants extracts,Combinatorial

Libraries

3-D ligand Databases

DockingLinking orBinding

Receptor-LigandComplex

Randomscreening synthesis

Lead molecule

3-D QSAR

Target EnzymeOR Receptor

3-D structure by Crystallography,NMR, electron microscopy OR

Homology Modeling

Redesign to improve

affinity, specificity etc.

Testing

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 DRUG ACTION

Substrate

ProteinLigand

BINDING

REACTION

FUNCTION

STRUCTURAL CHANGE

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

The Process

Identify disease protein Identify active siteDetermine structure

of Protein

Virtual Screening ofDrug Candidates

Synthesis of LeadCompounds

PharmacologicalTesting

Optimisation Clinical Trials Drug

Docking Protocol

contd...

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

Lead Optimization

Lead Lead OptimizationActive site

Express proteins with changes in amino acid sequencesIdentify amino acids involved in function

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…….

Virtual screening, to identify potential lead compounds from a large dataset

• Known structures of organic compounds

• Libraries of Virtual Compounds

• Programs calculate affinity for protein

• Narrow down to small number of possiblities

• Surface representation that efficiently represents the docking surface and identifies the regions of interest (cavities and protrusions)

• Surface matching that matches surfaces to optimize a binding score

Pose prediction• If we know exactly

where and how a known ligand binds...

– We can see which parts are important for binding

– We can suggest changes to improve affinity

– Avoid changes that will ‘clash’ with the protein

• 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)

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 is gaining 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 is accomplished by proteins interacting with themselves and with other molecular components

Modified Simple Algorithm and 3D Superposition and Alignment

Drug Discovery by Drug DesigningCase 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

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1

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7AccD5-NCI65828

1/[Malonyl-CoA]um-1

1/V

o (m

in-1

)[I] = 0.00[I] = 2.50[I] = 5.00[I] =10.00

TB ACCase, AccD5

Docking

The Computational Loop - Similarity Search

Structure-Based Drug Design Identified AccD5 Inhibitors

New TB drug lead

HO3S

NH2

N

N

OH

Why is this difficult?• Both molecules are flexible and may alter each other’s

structure as they interact:

• Hundreds to thousands of degrees of freedom (DOF)• Total possible conformations are astronomical

Trypsinogen

Trypsin

Chymotrypsinogen

Chymotrypsin

Duodenal Cell

Enterokinase

USES OF DOCKINGDrug targets Protein- ligand interactions that otherwise may be overlookedBetter understand the Machinery of Life

Enzyme-inhibitor classAntibody-antigen classOthers

Protein Therapies Engineered Protein EnzymesAlthough 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

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…….

Future Challenges For Docking

• Better Scoring Functions

• High-Throughput Screening

• Tractable Models of Flexibility

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

1. The algorithms can handle only a limited extent of backbone flexibility

2. The availability of selective and efficient scoring functions