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IN –SILICO DRUG TARGET DESIGNING FOR MIGRAINE UNDER GUIDANCE OF Mr. ARVIND SINGH  FACULTY BII,NOIDA,INDIA BY-  CHINMAYA MA...
INTRODUCTION <ul><li>In-silico  Drug Design  </li></ul><ul><li>In silico drug designing is defined as the identification o...
In silico  methods   <ul><li>Identifying drug targets via bioinformatics tools. </li></ul><ul><li>To analyze the target st...
Steps in Drug Designing
MIGRAINE <ul><li>Migraine is a neurological disorder .A  migraine  headache is a severe pain that is typically on one side...
SYMPTOMS OF MIGRAINE <ul><li>Intense pulsating or throbbing headache </li></ul><ul><li>Moderate to intense pain affecting ...
TYPES OF MIGRAINE <ul><li>Common Migraine (migraine without aura) </li></ul><ul><li>Classical Migraine (migraine with aura...
PATHOPHYSIOLOGY <ul><li>Depolarization Theory. </li></ul><ul><li>Vascular theory  </li></ul><ul><li>Serotonin theory </li>...
 
DRUGS PREVIOUSLY PRESCRIBED TO CURE MIGRAINE <ul><li>Paracetamol  - It is used to cure normal headaches but not effective ...
 
DESCRIPTION OF PROCESS WITH SOFTWARES USED   <ul><li>TAKING A PROTEIN SEQUENCE FROM NCBI FOR PROTEIN S(WHOSE DEFICIENCY CA...
BLASTP RESULTS
<ul><li>Then taking a known protein similar in nature i.e. P98118(for RABBIT). And performing the comparative modelling  t...
 
<ul><li>SINCE THE MODEL 2 IS HAVING THE MAXIMUM SEQUENCE IDENTITY OF 87%. ITS RAMACHANDRAN PLOT IS DRAWN TO PREDICT THE RE...
BETA SHEET ALPHA LEFTHELIX ALPHA HELIX
<ul><li>RAMACHANDRAN PLOT OF MODEL-2 </li></ul>COLOUR KEY GREEN - ALPHA   REGION BLUE - ADDITIONAL  ALLOWED REGIONS RED- G...
<ul><li>SINCE FURTHER INFORMATION ABOUT THE UNNAMED PROTEIN IS NOT AVAILABLE .THE SECOND APPROACH IS TAKEN BY CHOOSING A K...
<ul><li>SEQUENCE AS IN  DS VISUALISER </li></ul>
DESINING OF INHIBITOR(LIGAND) FOR THE PROTEIN MOLECULE <ul><li>WHAT IS LIGAND? </li></ul><ul><li>Ligand  is either an  ato...
PROPERTIES OF THE DRUGS THAT WERE CACULATED <ul><li>C log p:-   partition  (P) or  distribution coefficient  (D) is the ra...
TABLE CONTAINING LIGAND WITH THEIR PROPERTIES
FOR LIGAND DERIVATIVES <ul><li>D </li></ul>
DOCKING <ul><li>Docking  is a method which predicts the preferred orientation of one molecule to a second when  bound  to ...
RESULTS OF DOCKING <ul><li>RESULT FOR DOCKING SHOWING SUMATRIPTAN DERIVATIVE GIVING THE MINIMUM BINDING ENERGY VALUE.  </l...
DRUGS,THEIR DERIVATIVES AND THEIR BINDING ENERGY VALUE[EVALUE] -174.74 SUMATRIPTAN DERIVATIVES -162.74 SUMATRIPTAN -120.22...
RESULTS AND DISCUSSIONS
REFERENCES <ul><li>CLINICAL APPROACH TO HEADACHE IN CHILDREN AND PREVENTIVE  THERAPY OF MIGRAINE-KK SINHA(JIACM 2005;6(1):...
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In-Silico Drug Designing Approach

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Transcript of "In-Silico Drug Designing Approach"

  1. 1. IN –SILICO DRUG TARGET DESIGNING FOR MIGRAINE UNDER GUIDANCE OF Mr. ARVIND SINGH FACULTY BII,NOIDA,INDIA BY- CHINMAYA MAHAPATRA
  2. 2. INTRODUCTION <ul><li>In-silico Drug Design </li></ul><ul><li>In silico drug designing is defined as the identification of the drug target molecule by employing computational tools </li></ul>
  3. 3. In silico methods <ul><li>Identifying drug targets via bioinformatics tools. </li></ul><ul><li>To analyze the target structures for possible binding/ active sites. </li></ul><ul><li>Generating candidate molecules, checking for their drug likeness. </li></ul><ul><li>Docking these molecules with the target </li></ul><ul><li>Ranking them according to their binding affinites </li></ul><ul><li>Further lead optimization to improve binding characteristics </li></ul>
  4. 4. Steps in Drug Designing
  5. 5. MIGRAINE <ul><li>Migraine is a neurological disorder .A migraine headache is a severe pain that is typically on one side of the head but sometimes on both sides. </li></ul><ul><li>Migraines can occur at any time of the day and can last a few hours or up to one or two days. </li></ul><ul><li>Migraine attacks can be very intense, forcing the sufferer to abandon normal daily activities. </li></ul><ul><li>Migraine is commonly experienced between the ages of 15 and 55. </li></ul>
  6. 6. SYMPTOMS OF MIGRAINE <ul><li>Intense pulsating or throbbing headache </li></ul><ul><li>Moderate to intense pain affecting daily activities </li></ul><ul><li>Nausea, vomiting or diarrhea </li></ul><ul><li>Increased sensitivity to smells </li></ul><ul><li>Increased sensitivity to sounds </li></ul><ul><li>Increased sensitivity to light (photophobia) </li></ul><ul><li>Visual disturbances or ‘aura’ </li></ul>
  7. 7. TYPES OF MIGRAINE <ul><li>Common Migraine (migraine without aura) </li></ul><ul><li>Classical Migraine (migraine with aura) </li></ul><ul><li>Opthalmoplegic migraine </li></ul><ul><li>Hemiplegic migraine </li></ul><ul><li>Basilar type migraine </li></ul><ul><li>Abdominal migraine </li></ul><ul><li>Acephalgic migraine </li></ul>
  8. 8. PATHOPHYSIOLOGY <ul><li>Depolarization Theory. </li></ul><ul><li>Vascular theory </li></ul><ul><li>Serotonin theory </li></ul>
  9. 10. DRUGS PREVIOUSLY PRESCRIBED TO CURE MIGRAINE <ul><li>Paracetamol - It is used to cure normal headaches but not effective in acute cases. </li></ul><ul><li>Aspirin - Help relieve symtoms of nausea and help prevent vomiting. But effective only if taken early. </li></ul><ul><li>Sumatriptan - Best drug available </li></ul><ul><li>Naproxen -Taken with caffiene </li></ul><ul><li>Ibuprofen -Generally taken with aspirin to be effective </li></ul><ul><li>Ergotamine -Quite effective but has the side-effect that it itself is very nauseated </li></ul><ul><li>Feverfew -Herbal medicine </li></ul>
  10. 12. DESCRIPTION OF PROCESS WITH SOFTWARES USED <ul><li>TAKING A PROTEIN SEQUENCE FROM NCBI FOR PROTEIN S(WHOSE DEFICIENCY CAUSES MIGRAINE). </li></ul><ul><li>PROTEIN TAKEN IS BAF85683[Unnamed protein]. THEN PERFORMING ITS BLASTP. </li></ul><ul><li>BLASTP ( B asic L ocal A lignment S earch T ool For Protein) </li></ul><ul><li>Uses the BLAST algorithm to compare an amino acid query sequence against a protein sequence database . </li></ul>
  11. 13. BLASTP RESULTS
  12. 14. <ul><li>Then taking a known protein similar in nature i.e. P98118(for RABBIT). And performing the comparative modelling through using GENO-3D. </li></ul><ul><li>GENO-3D </li></ul><ul><li>GENO-3D i.e. Homology Modeling involves taking a known sequence with an unknown structure and mapping it against a known structure of one or several similar (homologous) proteins . </li></ul><ul><li>GENO-3D RESULTS </li></ul>
  13. 16. <ul><li>SINCE THE MODEL 2 IS HAVING THE MAXIMUM SEQUENCE IDENTITY OF 87%. ITS RAMACHANDRAN PLOT IS DRAWN TO PREDICT THE RESIDUES AND THE STEREOCHEMISTRY OF THE UNKNOWN PROTEIN. </li></ul><ul><li>RAMACHANDRAN PLOTS[USING PROCHECK SOFTWARE] </li></ul><ul><li>A Ramachandran plot is a way to visualize dihedral angles φ against ψ of amino acid residues in protein structure. It shows the possible conformations of φ and ψ angles for a polypeptide. </li></ul>
  14. 17. BETA SHEET ALPHA LEFTHELIX ALPHA HELIX
  15. 18. <ul><li>RAMACHANDRAN PLOT OF MODEL-2 </li></ul>COLOUR KEY GREEN - ALPHA REGION BLUE - ADDITIONAL ALLOWED REGIONS RED- GENEROUSLY ALLOWED REGIONS
  16. 19. <ul><li>SINCE FURTHER INFORMATION ABOUT THE UNNAMED PROTEIN IS NOT AVAILABLE .THE SECOND APPROACH IS TAKEN BY CHOOSING A KNOWN PROTEIN INVOLVED IN MIGRAINE IN THE PDB(PROTEIN DATA BANK). The protein is 2YX8( Crystal structure of the extracellular domain of human RAMP1 ). </li></ul><ul><li>DS VISUALISER </li></ul><ul><li>The structure of the protein is visualised through the DS VISUALIZER </li></ul>
  17. 20. <ul><li>SEQUENCE AS IN DS VISUALISER </li></ul>
  18. 21. DESINING OF INHIBITOR(LIGAND) FOR THE PROTEIN MOLECULE <ul><li>WHAT IS LIGAND? </li></ul><ul><li>Ligand is either an atom , ion , or molecule that bonds to a central metal, generally involving formal donation of one or more of its electrons . </li></ul><ul><li>DESINING OF LIGAND MOLECULE IN CHEMSKETCH </li></ul><ul><li>CHEMSKETCH :-ACD/ChemSketch is an advanced chemical drawing tool for drawing different chemical structures. </li></ul><ul><li>Five different drugs previously available were drawn along with their derivatives. The drugs are, </li></ul><ul><li>-Aspirin </li></ul><ul><li>-Ibuprofen </li></ul><ul><li>-Naproxen </li></ul><ul><li>-Paracetamol </li></ul><ul><li>-sumatriptan </li></ul>
  19. 22. PROPERTIES OF THE DRUGS THAT WERE CACULATED <ul><li>C log p:- partition (P) or distribution coefficient (D) is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium . Here ratio of (C octanol/C water) is taken. </li></ul><ul><li>MOLECULAR WEIGHT </li></ul><ul><li>HYDROGEN BOND DONOR AND ACCEPTORS. </li></ul><ul><li>CHECKING FOR CALCULATING THE LIPINSKI 5’ RULES. </li></ul><ul><li>LIPINSKI 5’ RULES ARE – </li></ul><ul><li>Not more than 5 hydrogen bond donors </li></ul><ul><li>Not more than 10 hydrogen bond acceptors </li></ul><ul><li>A molecular weight under 500 g/mol </li></ul><ul><li>A partition coefficient log P less than 5 </li></ul>
  20. 23. TABLE CONTAINING LIGAND WITH THEIR PROPERTIES
  21. 24. FOR LIGAND DERIVATIVES <ul><li>D </li></ul>
  22. 25. DOCKING <ul><li>Docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex . Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules </li></ul>
  23. 26. RESULTS OF DOCKING <ul><li>RESULT FOR DOCKING SHOWING SUMATRIPTAN DERIVATIVE GIVING THE MINIMUM BINDING ENERGY VALUE. </li></ul>
  24. 27. DRUGS,THEIR DERIVATIVES AND THEIR BINDING ENERGY VALUE[EVALUE] -174.74 SUMATRIPTAN DERIVATIVES -162.74 SUMATRIPTAN -120.22 PARACETAMOL DERIVATIVES -156.39 PARACETAMOL -161.20 NAPROXEN DERIVATIVES -156.39 NAPROXEN -155.34 IBUPROFEN DERIVATIVES -147.18 IBUPROFEN -128.96 ASPIRIN DERIVATIVES -136.47 ASPIRIN
  25. 28. RESULTS AND DISCUSSIONS
  26. 29. REFERENCES <ul><li>CLINICAL APPROACH TO HEADACHE IN CHILDREN AND PREVENTIVE THERAPY OF MIGRAINE-KK SINHA(JIACM 2005;6(1):64-2). </li></ul><ul><li>Migrainous Stroke in a Young Patient Associated with Protein S Deficiency - Sachin Kumar, Naresh Gupta, NP Singh, Sandeep Garg, Sameer Gulati(JIACM 2006;7(2):156-8) </li></ul><ul><li>Recent advances in the diagnosis and management of migraine- Peter J Goadsby(Journal of medical biology 13May 2008). </li></ul><ul><li>The Tight-Fit Brain - Study Reveals Brain Swelling As Cause of Migraine Headaches (New Research Unveiled at Physiological meeting at UCL-June 2006). </li></ul><ul><li>Gene influencing migraine- ScienceDaily (Apr. 21, 2008) (American Journal of Human Genetics) . </li></ul><ul><li>Protein may promote migraines -Andrew Russo-spring conference,2007 at the UI Carver College of Medicine,U.S.A </li></ul>
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