Computational rational design of Antiviral

Drugs for Swine flu

By
Raghunath Satpathy
MIRC LAB,MITS ENGINEERING COLLEGE ,
RAYAGADA
 Contents

Introduction
Materials and methods
Results and discussion
Conclusion
 Introduction

Swine flu now becomes a deadest

disease throughout the world.

Caused by 2009H1N1 virus

 Immunogenic Components of the
Influenza Virus
 Surface glycoprotein, 15 hemagglutinin (H1-H15), nine
neurominidases (N1-N9)
 H1-H3 and N1N2 established in humans
 Influenza characterized by combination of H and N
glycoproteins
 1917 pandemic - H5N1
 2004 avian influenza - H5N1
 2009 H1N1
 Human response is specific to hemagglutinin and
neurominidase glycoprotein
 STRATEGIES TO PREVENT FLU

 COVER MOUTH AND NOSE WHEN SNEEZING

 WASH HANDS FREQUENTLY WITH SOAP
AND WATER OR ALCOHOL
 AVOID TOUCHING EYES, NOSE AND MOUTH
 AVOID CONTACT WITH SICK PEOPLE
 TAKE ANTIVIRAL DRUGS IF PHYSICIAN
RECOMMENDS
 Common Drugs

Two FDA approved drugs


Zanamivir and Oseltamivir both are
neuraminidase inhibitors
 BACKGROUND

A recent report says that currently isolates

of H1N1 virus are resistant to presently
used neuraminidase inhibitor drugs like
Zanamivir and Oseltamivir
 objective
1)To understand at the molecular level how this new
H1N1 virus can be inhibited by the current anti-
influenza drugs
2)Homology modeling of a (selected) neuraminidase
protein
3)Docking with current drugs like Zanamivir and
Oseltamivir
4)From docking result find out the molecular part
involves in the binding process
5)Modification in drug molecule to enhance the
binding process
 Materials and methods

The sequence of a selected neuraminidase

enzyme was retrieved from NCBI having
ACESSION NO. GQ232095

Template structure was derived by PDB-

BLAST
Homology Modeling: How it
works

o Find template
o Align target
sequence
with template
o Generate model:
- add loops
- add side chains
o Refine model
Homology modelling (MODELLER)

Constraints are
Homology derived constraints
Distances and angles between
aligned positions should be similar
Stereochemical constraints
Bond lengths, bond angles,
dihedral angles, nonbonded atom-
atom contacts
Model are derived by minimizing restraints

Modeller: Sali & Blundell (1993

 Docking study
Drug and protein:
Lock and key mechanism,
blocking=>stopping of protein
function
What is Protein-Ligand Docking?

Definition:
Computationally predict the structures of
protein-ligand complexes from their
conformations and orientations. The
orientation that maximizes the interaction
reveals the most accurate structure of the
complex.
Importance of complexes
- structure -> function
 Docking studies

DOCKING WAS PERFORMED BY HEX 5.1

TOOL
Hex calculates the protein-ligand docking,
assuming the ligand is rigid, and it can
superpose pairs of molecules using only
knowledge of their 3D shapes
The superpostion program to use spherical
polar Fourier (SPF) correlations to accelerate
the calculations.
 Results
The sequence for the
neuraminidase protein having 468
amino acid was obtained from
NCBI having accession number gq
232095.

Template 3cye
E-value (0.0),
identity (88%)
Structure of model
 Structural details of the model

STRUCTURAL FEATURES INFORMATION

No. of residues 468

No. of atoms 3616

No. of Hydrogen bonds 252

No. of helices 3

No. of sheets 42

No. of turns 60
MODEL VALIDATION
(DOPE SCORE)
 MODEL VALIDATION
(ERRAT AND PROCHECK)
 DOPE, or Discrete Optimized Protein Energy, is a
statistical potential used to assess homology models
in protein structure prediction & it generates a
residue-by-residue energy profile for the input model
 ERRAT (QUALITY FACTOR 64.8)
 PROCHECK
% residues in favorable regions 81.7
% residues in additional residue 15.5
regions
% residues in generously regions 1.3
% residues in disallowed regions 1.5
 Docking study
 Docking was performed by HEX 5.1 tool
with the model neuraminidase and
original drug molecule viz. Oseltamivir and
Zanamivir.
 Docking by making different analogs(by
MARVIN SKETCH tool ) of the above drug
molecules.
 Docking with ZANAMIVIR and
analogs
Drugs docked E -values
Zanamivir -207.88
Zanamivir analog 1 -205.81
Zanamivir analog 2 -202.92
Zanamivir analog 3 -215.49
Zanamivir analog 4 -204.48
Zanamivir analog 5 -203.74
Zanamivir analog 6 -206.54
Zanamivir analog 7 -217.52
Zanamivir analog 8 -212.19
Zanamivir analog 9 -222.02

Zanamivir analog 10 -228.44

Docking with Oseltamivir and
analogs
Drugs docked E -values
Oseltamivir -193.53
Oseltamivir analog 1 -195.58
Oseltamivir analog 2 -201.36
Oseltamivir analog 3 -198.22
Oseltamivir analog 4 -198.83
Oseltamivir analog 5 -207.61
Oseltamivir analog 6 -208.03
Oseltamivir analog 7 -229.53

Oseltamivir analog 8 -231.21

Oseltamivir analog 9 -209.74
Oseltamivir analog 10 -224.83
Zanamivir and analog 10
(-CH OCH CH OH)
2 2 2
Oseltamivir and analog 8
(-CH COOH GROUP)
2
Docking of Zanamivir and analog 10
Docking of Oseltamivir and analog 8
 Conclusion

Docking results indicate that the analog 8 in case of

Oseltamivir and analog 10 in case of Zanamivir show
more potent binding activity than the original drugs,
this corresponds to inhibition activity against the viral
neuraminidase.

This type of analysis show that the some of the

modified drugs having more potential activity than the
original one may be used as probable lead molecule .
 NEXT …
QSAR analysis
Molecular assembly that
interacts with the drug
activity
 Resources
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enigma,” Cell, vol 136, pp.402-410, 2009.
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Farzan M , "Influenza A virus neuraminidase limits
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2007.
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protein structures: patterns of non bonded atomic
interactions” Protein Sci vol 2, pp. 1511–1519, 1993
 Contd..
5) Virupakshaiah DBM, Chandrakanth Kelmani,
Rachanagouda Patil, and Prasad Hegade, Computer
Aided Docking Studies on Antiviral Drugs for SARS
“PWASET, vol 24, pp. 297-299, 2008.

6) D.W. Ritchie,” Evaluation of Protein Docking

Predictions Using Hex 3.1 in CAPRI Rounds 1 and 2:
PROTEINS,” Struct. Funct. Genet. vol 52 pp 98-106.
2003
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