hcv polymerase inhibitor docking by discovery studio

Polymerase Inhibitors

Faculty Of Pharmacy ASUDrug Design Course

By: Marina Adel Ibrahim

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.

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!

Types of Inhibitors…

NS5B inhibitors

Nucleoside analogue

polymerase inhibitors

Non-nucleoside polymerase inhibitors

Non-nucleoside polymerase inhibitors…

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

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.

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.

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

OO S

O

O

CH3

N

NH2

Cl

N

NH

O

O

NH S

O

ONH S

O

O

CH3

F

Cl

N

NHNH

O

O

NH S

O

ONH S

O

O

CH3

N

NH2

O

Cl

N

NH

OO

NH S

O

O

NH S

O

O

CH3

S

O

F

Cl

N

NH

O

O

NH S

O

O CH3

F

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!!!

Docking results…

Docking results…

Docking results…

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.

2D interaction…Molecule-8 (highest Score)

3D interaction…

2D interaction of all other modifications in descending order acc. to

their scores…Molecule-7 Molecule-5Molecule-1(lead)

2D interaction of all other modifications in descending order acc. to

their scores…Molecule-6Molecule-4 Molecule-3

2D interaction of all other modifications in descending order acc. to

their scores…Molecule-2 Molecule-9 (lowest Score)

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).

References…1 .New therapeutic strategies in HCV: polymerase inhibitors - Liver International

ISSN 1478-3223By: Ludmila Gerber, Tania M. Welzel and Stefan Zeuzem

2 .Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 acylSulfonamides - Bioorganic & Medicinal Chemistry Letters 22 (2012) 713–717By: Gopinadhan N. Anilkumar

3 .Protein Data Bank (PDB) ::// . .http www rcsb org4 .WHO. Hepatitis C: Available at

:// . . / / / / 2003/ /http www who int csr disease hepatitis whocdscsrlyo en inde3.x 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 al6 .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