lectures 2 3 (receptors)
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New Methods for Drug Dscovery
Lectures 2-3Drug Targets (Receptors)
DOSEDRUG IN TISSUESDRUG IN SYSTEMIC CIRCULATIONEXCRETION AND METABOLISMABSORPTION ELIMINATIONDISTRIBUTION
ADME
Cell Membrane Lipids ProteinsReceptorsEnzymesCarrier proteinsStructural proteinsNucleic acidsDNARNACarbohydratesCell surface carbohydratesAntigen and recognition molecules
Drug Targets
Konrad H. Bleicher, Hans-Joachim Bhm, Klaus Mller & Alexander I. AlanineNature Reviews Drug Discovery2,369-378(May 2003)
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Receptors
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Drug-Receptor Interactions
1. Ionic (Electrostatic) Interactions
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Drug-Receptor Interactions
Ion-Dipole and Dipole- Dipole Interactions
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Drug-Receptor InteractionsHydrogen Bonds
Intramolecular H. bonding becomes important if involved in stabilizing the conformation necessary for binding and activity 7
Drug-Receptor Interactions
Intramolecular H. bonding becomes important if involved in stabilizing the conformation necessary for binding and activity Ortho is a wek antibacterial while the para is a strong antibacterial8
Drug-Receptor Interactions
Intramolecular H. bonding becomes important if involved in stabilizing the conformation necessary for binding and activity Ortho is a wek antibacterial while the para is a strong antibacterial9
Drug-Receptor Interactions
Intramolecular H. bonding becomes important if involved in stabilizing the conformation necessary for binding and activity Ortho is a wek antibacterial while the para is a strong antibacterial10
Drug-Receptor InteractionsCharge-Transfer Hydrophobic Interactions
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Drug-Receptor Interactions- stacking Cation- Interation
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Drug-Receptor InteractionsHalogen Bonding
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Drug-Receptor Interactions
Constitutive Receptor Activity
Drug-Receptor Interactions
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Theories of Drug-Receptor InteractionsOccupancy TheoryThe intensity of the bodys response to the drug is directly related to the number of receptors occupied by the drug.The maximum response occurs when all of the receptors have drug molecules attached.
Theories of Drug-Receptor InteractionsRate TheoryPharmacological response is not dependent on drug-receptor complex concentration but rather depends upon rate of association of drug and receptor.
Drug-Receptor InteractionsTwo-state (Multi-state) Receptor ModelR and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor.Full agonists bind only to R*Partial agonists bind preferentially to R*Full inverse agonists bind only to RPartial inverse agonists bind preferentially to RAntagonists have equal affinities for both R and R* (no effect on basal activity)In the multi-state model there is more than one R state to account for variable agonist and inverse agonist behavior for the same receptor type.
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Drug Chirality
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Conformational Isomers
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Conformational Isomers
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Diastereomers
Receptor ChiralityRoger A.H. Adan. Nature, Volume 27, Issue 4, 2006, 183186
Topographical and Stereochemical Considerations
Topographical and Stereochemical Considerations
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Allosteric Modulators
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