Drug Target Identification for

Hepatitis-B

Guided by: Presented By: Arvind Singh Kamal Sharma

MSc. Biotechnology

Introduction to Hepatitis B

Hepatitis is a general term for inflammation of the liver.

Hepatitis B is liver infection caused by infection with HBV.

HBV is a blood borne virus.Infection has Two Phases:

Acute Hepatitis (Fulminant Hepatitis) Chronic Hepatitis (people called as chronic

carriers)

The infection may lead to:Liver Failure.Hepatocellular carcinoma.Thus ultimately lead to death.

Half of all people infected with HBV have no symptoms but others may include:FatigueNausea and vomittingItching all overJaundice

Treatment & Medication

Acute Hepatitis B usually go away itself.There are no medication that can prevent acute

hepatitis B from becoming chronic.There are certain antiviral medications which

stop or slow viral replication in the body.Interferon-α (Flue like side effect)LamivudineTelbivudineHepsaraBaraclude

Organization of HBV

Schematic section through an infectious hepatitis B virion. The envelope contains the surface proteins L, M, and S. The preSdomain of L occurs in an inward and an outward topology. The irregularly shaped object represents the cellular chaperone Hsc70 that copurifies with virions and S particles. The HBV genome inside the capsid is present as partially double-stranded circular DNA. The 5)- end of the complete (–)-DNA strand is covalently linked to the TP domain of P protein.

Viral Replication cycle The virus attaches to

membrane rectors of host cell.

cccDNA formation occurs mRNA synthesis occurs

and is ransported to cytoplasm.

P-protein synthesis occurs and encapsulisation occurs.

Target Identified

L,M,S envelop: This are derieved from host cell, so not reliable.

Core protein can be a target coded by viral genome.

P protein: (DNA polymerase, reverse transcriptase) present inside the core.

Thus, P protein can be a potent target.The protein can be targeted at two sites in its

replication cycle as shown in figure:

IInd site for drug targeting

Ist site for drug targeting

Steps in targeting P-protein

Synthesis of Drug derivatives. Searching for properties of the

Derivatives. Searching for structure of P-protein. Docking. Analysis of result following Lipinski

rule and minimum Etotal.

Drug derivatives Synthesis

The drugs lamivudine and telbivudine are the recently approved drugs.

There derivatives are created using chemsketch.

O N

NH

S

OO

OCH3

O

Lamivudine Derivative

N

NH

O

OO

OH

OH

S

Telbivudine Derivative

Drug Derivative Properties

Lipinski’s rule:

– Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)

– Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)

– A molecular weight under 500 g/mol – A partition coefficient log P less than 5

The properties are now searched from Pubchem

Searching for structure of P-protein

The structure is searched from PDB The id of Structure obtained is used

to search the same structure from MMDB

Docking

The process of docking is done use Hex 4.5 tool.

The result are saved for the analysis.

Result

The table above shows that best drug derivative is telbivudine derivative but its partition coifficient value is negative than comes the lamivudine derivative is better drugs derivative following lipinski’s rule.

Thus, lamivudine can be a potent drug target against hepatitis-B in future.

Thank You………….