In-Silico Drug Designing Approach
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In-Silico Drug Designing Approach

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In-Silico Drug Designing Approach In-Silico Drug Designing Approach Presentation Transcript

  • IN –SILICO DRUG TARGET DESIGNING FOR MIGRAINE UNDER GUIDANCE OF Mr. ARVIND SINGH FACULTY BII,NOIDA,INDIA BY- CHINMAYA MAHAPATRA
  • INTRODUCTION
    • In-silico Drug Design
    • In silico drug designing is defined as the identification of the drug target molecule by employing computational tools
  • In silico methods
    • Identifying drug targets via bioinformatics tools.
    • To analyze the target structures for possible binding/ active sites.
    • Generating candidate molecules, checking for their drug likeness.
    • Docking these molecules with the target
    • Ranking them according to their binding affinites
    • Further lead optimization to improve binding characteristics
  • Steps in Drug Designing
  • MIGRAINE
    • 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.
    • Migraines can occur at any time of the day and can last a few hours or up to one or two days.
    • Migraine attacks can be very intense, forcing the sufferer to abandon normal daily activities.
    • Migraine is commonly experienced between the ages of 15 and 55.
  • SYMPTOMS OF MIGRAINE
    • Intense pulsating or throbbing headache
    • Moderate to intense pain affecting daily activities
    • Nausea, vomiting or diarrhea
    • Increased sensitivity to smells
    • Increased sensitivity to sounds
    • Increased sensitivity to light (photophobia)
    • Visual disturbances or ‘aura’
  • TYPES OF MIGRAINE
    • Common Migraine (migraine without aura)
    • Classical Migraine (migraine with aura)
    • Opthalmoplegic migraine
    • Hemiplegic migraine
    • Basilar type migraine
    • Abdominal migraine
    • Acephalgic migraine
  • PATHOPHYSIOLOGY
    • Depolarization Theory.
    • Vascular theory
    • Serotonin theory
  •  
  • DRUGS PREVIOUSLY PRESCRIBED TO CURE MIGRAINE
    • Paracetamol - It is used to cure normal headaches but not effective in acute cases.
    • Aspirin - Help relieve symtoms of nausea and help prevent vomiting. But effective only if taken early.
    • Sumatriptan - Best drug available
    • Naproxen -Taken with caffiene
    • Ibuprofen -Generally taken with aspirin to be effective
    • Ergotamine -Quite effective but has the side-effect that it itself is very nauseated
    • Feverfew -Herbal medicine
  •  
  • DESCRIPTION OF PROCESS WITH SOFTWARES USED
    • TAKING A PROTEIN SEQUENCE FROM NCBI FOR PROTEIN S(WHOSE DEFICIENCY CAUSES MIGRAINE).
    • PROTEIN TAKEN IS BAF85683[Unnamed protein]. THEN PERFORMING ITS BLASTP.
    • BLASTP ( B asic L ocal A lignment S earch T ool For Protein)
    • Uses the BLAST algorithm to compare an amino acid query sequence against a protein sequence database .
  • BLASTP RESULTS
    • Then taking a known protein similar in nature i.e. P98118(for RABBIT). And performing the comparative modelling through using GENO-3D.
    • GENO-3D
    • 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 .
    • GENO-3D RESULTS
  •  
    • 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.
    • RAMACHANDRAN PLOTS[USING PROCHECK SOFTWARE]
    • 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.
  • BETA SHEET ALPHA LEFTHELIX ALPHA HELIX
    • RAMACHANDRAN PLOT OF MODEL-2
    COLOUR KEY GREEN - ALPHA REGION BLUE - ADDITIONAL ALLOWED REGIONS RED- GENEROUSLY ALLOWED REGIONS
    • 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 ).
    • DS VISUALISER
    • The structure of the protein is visualised through the DS VISUALIZER
    • SEQUENCE AS IN DS VISUALISER
  • DESINING OF INHIBITOR(LIGAND) FOR THE PROTEIN MOLECULE
    • WHAT IS LIGAND?
    • 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 .
    • DESINING OF LIGAND MOLECULE IN CHEMSKETCH
    • CHEMSKETCH :-ACD/ChemSketch is an advanced chemical drawing tool for drawing different chemical structures.
    • Five different drugs previously available were drawn along with their derivatives. The drugs are,
    • -Aspirin
    • -Ibuprofen
    • -Naproxen
    • -Paracetamol
    • -sumatriptan
  • PROPERTIES OF THE DRUGS THAT WERE CACULATED
    • 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.
    • MOLECULAR WEIGHT
    • HYDROGEN BOND DONOR AND ACCEPTORS.
    • CHECKING FOR CALCULATING THE LIPINSKI 5’ RULES.
    • LIPINSKI 5’ RULES ARE –
    • Not more than 5 hydrogen bond donors
    • Not more than 10 hydrogen bond acceptors
    • A molecular weight under 500 g/mol
    • A partition coefficient log P less than 5
  • TABLE CONTAINING LIGAND WITH THEIR PROPERTIES
  • FOR LIGAND DERIVATIVES
    • D
  • DOCKING
    • 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
  • RESULTS OF DOCKING
    • RESULT FOR DOCKING SHOWING SUMATRIPTAN DERIVATIVE GIVING THE MINIMUM BINDING ENERGY VALUE.
  • 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
  • RESULTS AND DISCUSSIONS
  • REFERENCES
    • CLINICAL APPROACH TO HEADACHE IN CHILDREN AND PREVENTIVE THERAPY OF MIGRAINE-KK SINHA(JIACM 2005;6(1):64-2).
    • 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)
    • Recent advances in the diagnosis and management of migraine- Peter J Goadsby(Journal of medical biology 13May 2008).
    • The Tight-Fit Brain - Study Reveals Brain Swelling As Cause of Migraine Headaches (New Research Unveiled at Physiological meeting at UCL-June 2006).
    • Gene influencing migraine- ScienceDaily (Apr. 21, 2008) (American Journal of Human Genetics) .
    • Protein may promote migraines -Andrew Russo-spring conference,2007 at the UI Carver College of Medicine,U.S.A