In-Silico Drug Designing ApproachPresentation Transcript
IN –SILICO DRUG TARGET DESIGNING FOR MIGRAINE UNDER GUIDANCE OF Mr. ARVIND SINGH FACULTY BII,NOIDA,INDIA BY- CHINMAYA MAHAPATRA
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 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)
Basilar type migraine
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 .
Then taking a known protein similar in nature i.e. P98118(for RABBIT). And performing the comparative modelling through using 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 .
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 ).
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,
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.
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
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.