Example for docking using discovery studio

1. Polymerase Inhibitors

2. A little Introduction…
• You Probably Know already that Egypt has the
largest epidemic of HCV in the world !!!
(estimated among adults at 10 and 20% in urban and rural
areas, respectively).
•The origin of the epidemic has been attributed to mass
campaigns of parenteral anti-schistosomiasis treatment in
rural areas in the 1960s–70s.
• Since then, the virus has continued to spread, mainly
through intravenous injections and other medical procedures
and the incidence of new infections remains the highest,
worldwide.

3. HCV Polymerase Role…
HCV Polymerase (NS5B Protein) has the key
function of replicating the HCV’s viral RNA by using
the viral positive RNA strand as its template and
catalyzes the polymerization of ribonucleoside
triphosphates (rNTP) during RNA replication. That’s
why Several inhibitors of the viral RNA-dependent
RNA polymerase have proven effectiveness in
clinical trials.
Let’s Start!

4. Types of Inhibitors…

5. Non-nucleoside polymerase inhibitors…
Non-nucleoside inhibitors bind
outside the active site and target
allosteric sites on the surface of
the enzyme.

6. Non-nucleoside polymerase inhibitors…
Several crystal structures of NS5B
polymerase in several crystalline
forms have been determined. Its
structure can be represented by a
right hand shape with palm, thumb
and fingers colored red, green, and
blue, respectively.

7. Indole C2 Acyl Sulfonamides…
They are non-nucleoside palm site inhibitors of HCV
NS5B polymerase.
Let’s check together our lead compound!
We decided on using this lead after checking into The
PDB to make sure it’s available in complex with the HCV
polymerase, then we made variable modifications on it’s
structure!!!
SAR:
*The indole acyl sulfonamide nucleus is essential
pharmacophore.
*Addition of polar groups (HBDs & HBAs) increases the
activity.
*removal of the phenyl sulfonamide & addition of
hydrophobic substituents instead resulted in decreased
activity.

8. Proposed modifications…
Cl
N
NH
O
O
NH S
O
O
CH3
N
NH2
Cl
N
NH
O
O
NH S
O
O
N
NH2
Cl
N
NH
O
O
NH S
O
O
F
Cl
N
NH
O
O
NH S
O
O
O S
O
O
CH3
N
NH2
Cl
N
NH
O
O
NH S
O
O
NH S
O
O
CH3
F
Cl
N
NH
NH
O
O
NH S
O
O
NH S
O
O
CH3
N
NH2
O
Cl
N
NH
O
O
NH S
O
O
NH S
O
O
CH3
S
O
F
Cl
N
NH
O
O
NH S
O
O
CH3
F

9. The use of ADS…
We used Accelrys Discovery Studio
for preparing the protein &
applying docking to our
ligands…the results are to be
demonstrated on the following
slides!!!

10. Docking results…

11. Docking results…

12. Docking results…

13. Discussion…
*From the results Molecule-8 had the highest LibDockScore, even higher
than the lead followed by Molecule-7 while Molecule-9 came last.
*After checking Molecule-8 2D interaction diagram with the binding site,
we noticed that the higher score that was obtained by Molecule-8 is
mainly due to the hydrophobic interaction between the newly
introduced thiophene ring and Tyr415 even though the bi-dentate
hydrogen bonding interactions with the Tyr-448 and Gln-446 that was a
unique feature of the lead wasn't preserved.
*We also noticed that the addition of hydrophobic substituents to the
acyl sulfonamide moiety instead of the phenyl sulfonamide resulted in
lower LibDockScores as with ethyl in Molecule-9, methyl in Molecule-2
and cyclopropyl in Molecule-3.

14. 2D interaction… 3D interaction…

15. 2D interaction of all other modifications in descending order acc. to
their scores…

16. 2D interaction of all other modifications in descending order acc. to
their scores…

17. 2D interaction of all other modifications in descending order acc. to
their scores…

18. Conculsion…
*As already know the current HCV standard of care is
associated with many side effects, that's why the
discovery of small potent inhibitors to HCV replication
is a valuable topic for research.
*HCV NS5B Polymerase has variety of inhibitors which
opens doors for interested researchers, especially with
the use of computer-aided drug design (CADD) that
helped our team test the results of the modifications
applied to the lead and find a new indole acyl
sulfonamide derivative with higher LibDockScore
than the lead (Molecule-8).

19. References…
1. New therapeutic strategies in HCV: polymerase inhibitors - Liver International
ISSN 1478-3223
By: Ludmila Gerber, Tania M. Welzel and Stefan Zeuzem
2. Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 acyl
Sulfonamides - Bioorganic & Medicinal Chemistry Letters 22 (2012) 713–717
By: Gopinadhan N. Anilkumar
3. Protein Data Bank (PDB): http://www.rcsb.org
4. WHO. Hepatitis C: Available at
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index3.html
5. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral
Hepatitis 2009; 16: 75–90.
By: Zeuzem S, Berg T, Moeller B, et al
6. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus Proc
Nat Acad Sci 1996; 96: 13034–9.
By: Bressanelli S, Tomei L, Incitti I, et al