Structural

Basis of Specific Enzyme Inhibition:

Imatinib Interaction with the BCR-Abl Kinase
Source: David E. Golan, Armen H. Tashjian, Jr. Ehrin J. Armstrong, April W. Armstrong.
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 3rd Ed.
Determinants of Drug Specific Binding
to a Receptor
•  Hydrophobicity
•  Ionization state (pKa)
•  Conformation
•  Stereochemistry (S vs. R enantiomers)
1The K is the concentration for 50% saturation of the receptors and is inversely proportionate to the affinity of the drug for the receptors.
d
Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Clin Pharmacol 1990;38:S82.
Impact of Drug Binding on the Receptor
http://www.cellbiol.net/ste/rpimages.php
 Drug Selectivity
Determinants
1.Some receptors are more limited 2. Different receptor-effector system in
in their distribution = Localized the same tissues
receptors.
Ex. Cardiac pacemaker cells are relatively
Ex. BCR-Abl protein – not expressed more sensitive to the effects of calcium
in normal (noncancerous) cells channel blocking agents than are cardiac
target for Imatinib ventricular muscle cells.
 Major Types of Drug Receptors
•  A – Transmembrane ion channels
•  B – Transmembrane receptors coupled to intracellular G proteins
•  C – Transmembrane receptors with enzymatic cytosolic formation
•  D – Intracellular receptors
•  Extracellular enzymes
•  Cell-surface adhesion receptors
Source: David E. Golan, Armen H. Tashjian, Jr. Ehrin J. Armstrong, April W. Armstrong.
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 3rd Ed.