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)
3
Receptors
4
Drug-Receptor Interactions
1. Ionic (Electrostatic) Interactions
5
Drug-Receptor Interactions
Ion-Dipole and Dipole- Dipole Interactions
6
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
11
Drug-Receptor Interactions- stacking Cation- Interation
12
Drug-Receptor InteractionsHalogen Bonding
13
Drug-Receptor Interactions
Constitutive Receptor Activity
Drug-Receptor Interactions
16
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.
19
Drug Chirality
20
Conformational Isomers
21
Conformational Isomers
22
Diastereomers
Receptor ChiralityRoger A.H. Adan. Nature, Volume 27, Issue 4,
2006, 183186
Topographical and Stereochemical Considerations
Topographical and Stereochemical Considerations
26
Allosteric Modulators
