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Drug Target Identification

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Drug Target Identification

  1. 1. Drug Target Identification for Hepatitis - B Guided by: Presented By : Arvind Singh Kamal Sharma MSc. Biotechnology
  2. 2. Introduction to Hepatitis B <ul><li>Hepatitis is a general term for inflammation of the liver. </li></ul><ul><li>Hepatitis B is liver infection caused by infection with HBV. </li></ul><ul><li>HBV is a blood borne virus. </li></ul><ul><li>Infection has Two Phases: </li></ul><ul><ul><li>Acute Hepatitis (Fulminant Hepatitis) </li></ul></ul><ul><ul><li>Chronic Hepatitis (people called as chronic carriers) </li></ul></ul>
  3. 3. <ul><li>The infection may lead to: </li></ul><ul><ul><li>Liver Failure. </li></ul></ul><ul><ul><li>Hepatocellular carcinoma. </li></ul></ul><ul><ul><li>Thus ultimately lead to death. </li></ul></ul><ul><li>Half of all people infected with HBV have no symptoms but others may include: </li></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Nausea and vomitting </li></ul></ul><ul><ul><li>Itching all over </li></ul></ul><ul><ul><li>Jaundice </li></ul></ul>
  4. 4. Treatment & Medication <ul><li>Acute Hepatitis B usually go away itself. </li></ul><ul><li>There are no medication that can prevent acute hepatitis B from becoming chronic. </li></ul><ul><li>There are certain antiviral medications which stop or slow viral replication in the body. </li></ul><ul><ul><li>Interferon- α ( Flue like side effect ) </li></ul></ul><ul><ul><li>Lamivudine </li></ul></ul><ul><ul><li>Telbivudine </li></ul></ul><ul><ul><li>Hepsara </li></ul></ul><ul><ul><li>Baraclude </li></ul></ul>
  5. 5. Organization of HBV <ul><li>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. </li></ul>
  6. 6. Viral Replication cycle <ul><li>The virus attaches to membrane rectors of host cell. </li></ul><ul><li>cccDNA formation occurs </li></ul><ul><li>mRNA synthesis occurs and is ransported to cytoplasm. </li></ul><ul><li>P-protein synthesis occurs and encapsulisation occurs. </li></ul>
  7. 7. Target Identified <ul><ul><li>L,M,S envelop: This are derieved from host cell, so not reliable. </li></ul></ul><ul><ul><li>Core protein can be a target coded by viral genome. </li></ul></ul><ul><ul><li>P protein: (DNA polymerase, reverse transcriptase) present inside the core. </li></ul></ul><ul><ul><li>Thus, P protein can be a potent target. </li></ul></ul><ul><ul><li>The protein can be targeted at two sites in its replication cycle as shown in figure: </li></ul></ul>
  8. 8. IInd site for drug targeting Ist site for drug targeting
  9. 9. Steps in targeting P-protein <ul><li>Synthesis of Drug derivatives. </li></ul><ul><li>Searching for properties of the Derivatives. </li></ul><ul><li>Searching for structure of P-protein. </li></ul><ul><li>Docking. </li></ul><ul><li>Analysis of result following Lipinski rule and minimum Etotal. </li></ul>
  10. 10. Drug derivatives Synthesis <ul><li>The drugs lamivudine and telbivudine are the recently approved drugs. </li></ul><ul><li>There derivatives are created using chemsketch. </li></ul>Lamivudine Derivative Telbivudine Derivative
  11. 11. Drug Derivative Properties <ul><li>Lipinski’s rule: </li></ul><ul><ul><li>Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms) </li></ul></ul><ul><ul><li>Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms) </li></ul></ul><ul><ul><li>A molecular weight under 500 g/mol </li></ul></ul><ul><ul><li>A partition coefficient log P less than 5 </li></ul></ul><ul><li>The properties are now searched from Pubchem </li></ul>
  12. 12. Searching for structure of P-protein <ul><li>The structure is searched from PDB </li></ul><ul><li>The id of Structure obtained is used to search the same structure from MMDB </li></ul>
  13. 13. Docking <ul><li>The process of docking is done use Hex 4.5 tool. </li></ul><ul><li>The result are saved for the analysis. </li></ul>
  14. 14. Result
  15. 15. <ul><li>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. </li></ul><ul><li>Thus, lamivudine can be a potent drug target against hepatitis-B in future. </li></ul>
  16. 16. <ul><li>Thank You…………. </li></ul>

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