Lecture 1

Front 1

what are the protein structures?

Back 1

Protein Structure

Primary, secondary, tertiary and quaternary structure

Front 2

describe the primary structure

Back 2

Primary structure:

determined by the αα sequence in the polypeptide chain.

Front 3

describe the secondary structure

Back 3

Secondary structure:

determined by the interaction of ‘+’ charged H+ with ‘-’ charged oxygen atoms on carbons from the same polypeptide chain.

e.g. α helix & β ‘pleated’ sheet.

Front 4

describe the tertiary structure

Back 4

Tertiary structure:

is determined by the interactions of amino acids that are relatively far apart on the protein backbone. Interactions, include ionic bonds and covalent disulfide linkages (among others).

Front 5

describe the quaternary

structure

Back 5

Quaternary structure:

determined by the binding interactions among two or more independent protein subunits.

Front 6

explain the mechanism of the

hydrophobic parts of a protein. *

Back 6

Hydrophobic parts

of a protein are often drawn to the inside of a protein or protected by the lipid bi-layer.

Front 7

explain the mechanism of the

hydrophilic parts of a protein.

Back 7

Hydrophilic parts

of a protein are often drawn to the outside of a protein.

The binding site is the site of the receptor at which a drug binds.

The favorability of a drug for its receptor is

affinity.

Front 8

explain Van der Waals forces

Back 8

Van der Waals forces

result from polarity in a molecular induced by shifting its electron density in response to close proximity of another molecule.

e.g. Hydrogen bonds

Front 9

explain Covalent Bonds

Back 9

Covalent bonds result from sharing a pair of electrons between two atoms.RARELY is drug binding caused by a single type of interaction.The molecular structure dictates the physical and chemical properties that contribute to specific binding.

Other important factors include: hydrophobicity, ionization state pKa, confirmation & and stereochemistry.

Front 10

give an example of a

stereoisomer resulting from

covalent bonding *

Back 10

Warfarin:

enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right

Hint 10

Front 11

Case 1: BCR-Abl tyrosine kinase & imatinib p3

Back 11

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Hint 11

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Front 12

what is Imatinib (INN)? *

Back 12

Imatinib (INN):

a. Gleevec (Canada, South Africa and the USA)b. Glivec (Australia, Europe and Latin America)aka STI-571,

A tyrosine-kinase inhibitor used in the

treatment of multiplecancers, most

notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Hint 12

Front 13

describe the Structural Basis of Specific Enzyme Inhibition *

Back 13

A. BCR-Abl tyrosine kinase. An analogue of imatinib, a specific inhibitor of the BCR-Abl tyrosine kinase, is shown.

B. Interactions between the drug and amino acid (αα) residues in the BCR-Abl protein. Hydrogen bonds (dashed lines), while van der Waals interactions (halos) are shown.

C. Interaction of the drug (blue) with the BCR-Abl protein (gray) inhibits phosphorylation of the activation loop (green-ribbon).

Hint 13

Front 14

Some Pharmacodynamics:

Back 14

Hint 14

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Front 15

Agonists to and activate their targets causing what?

Back 15

Agonists to and activate their targets causing a change in activity.

Front 16

what is Super agonist capable of?

Back 16

Super agonist is capable of activating target to greater than the maximum extent.

Front 17

what does Full agonists bind to and activate?

Back 17

Full agonists bind to and activate their targets to the maximal extent possible.

E.g. isoproterenol, which mimics the action of adrenaline at β adrenoreceptors.

Hint 17

*

Front 18

partial agonists produce what?

Back 18

Partial Agonists produce a submaximal response in binding tot their targets. E.g. buprenorphine are used to treat opiate dependence.

Front 19

Inverse agonists cause what?

Back 19

Inverse agonists cause constitutively active targets to become inactive. cannabinoid inverse agonist rimonabant.

Front 20

Irreversible agonist is what type of agonist?

Back 20

Irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds. in such a manner that the receptor is permanently activate

Front 21

Antagonist inhibitor has the amility to do what?

Back 21

Antagonist inhibitor the ability of the target to be activated (or inactivated by physiologic (native) or pharmacologic (exogenous) agonists.

Front 22

Competitive antagonists do what?

Back 22

Competitive antagonists: drugs that directly block physiologic agonists

Hint 22

*

Front 23

Uncompetitive antagonists do what?

Back 23

Uncompetitive antagonists, those that don’t compete for binding of the agonist, but affect binding by leading to conformational change in the target.

Front 24

4-Major Types of

Drug-Receptor Interactions

Back 24

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Hint 24

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Front 25

type a drugs bind to?

Back 25

A. Drugs can bind ion channels, causing an alteration in conductance.

Front 26

type b drugs bind to?

Back 26

B. Heptahelical/7-transmembrane receptors coupled to intracellular G proteins.

Front 27

type c drugs bind to?

Back 27

C. Drugs can bind to the extracellular domain of a transmembrane receptor and cause a change in signaling within the cell by activating or inhibiting an enzymatic intracellular domain of the same receptor molecule.

Front 28

type d drugs bind to?

Back 28

D. Drugs can diffuse through the plasma membrane and bind to cytoplasmic or nuclear receptors. This is often the pathway used by lipophilic drugs (e.g., drugs that bind to steroid hormone receptors).

Alternatively, drugs can inhibit enzymes in the extracellular space without the need to cross the plasma membrane (not shown).

Front 29

Two important classes of drugs that act by altering the conductance of ion channels are what?
*

Back 29

Two important classes of drugs that act by altering the conductance of ion channels:

(i)local anaesthetics & the

(ii)benzodiazepines.

Hint 29

Front 30

Local anaesthetics does what?*

Back 30

Local anaesthetics, block (sodium) Na+ channel signalling in neurons that transmit pain signals form the PNS to the CNS.

Front 31

how does

Benzodiazapenes act?

*

Back 31

Benzodiazapenes act by inhibiting neurotransmission in the CNS by helping the gamma-aminobutyric acid (GABA) to increase the conductance of Chloride ions.

Front 32

Ligand-Gated Nicotinic Acetylcholine Receptor

Back 32

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Hint 32

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Front 33

A. The plasma membrane acetylcholine (ACh) receptor is composed of what?

Back 33

A. The plasma membrane acetylcholine (ACh) receptor is composed of:

two α subunits, a β subunit, as well as a γ & δ subunits.

Front 34

in the absence of plasma membrane acetylcholine (ACh) receptor what happens?

Back 34

B. The γ subunit has been removed to show an internal schematic view of the receptor. In the absence of ACh, the ‘gate’ is closed.

Front 35

what happens When ACh is bound to both α subunits?

Back 35

C. When ACh is bound to both α subunits, the channel opens, and Na+ can pass down its concentration gradient into the cell.

Front 36

table for Major G- Proteins and example of their actions.

Back 36

Front 37

how does Receptor-Mediated G Protein Activate?

Back 37

Front 38

Transmembrane Receptors with Enzymatic Cytosolic

Domains

Back 38

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Hint 38

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Front 39

how does Receptor tyrosine kinases work?

Back 39

Receptor tyrosine kinases

Upon ligand-induced activation, these receptors dimerize and transphosphorylate tyrosine residues in the receptor and, often, on target cytosolic proteins.

Front 40

how does Tyrosine phosphatases work?

Back 40

Tyrosine phosphatases.

These receptors dephosphorylate tyrosine residues either on other transmembrane receptors or on cytosolic proteins. Many cells of the immune system have receptor tyrosine phosphatases.

Front 41

how does Nonreceptor tyrosine kinases work?

Back 41

C.Nonreceptor tyrosine kinases.

Some tyrosine kinase-associated receptors lack a definitive enzymatic domain, but binding of ligand to the receptor triggers activation of receptor-associated protein kinases that then phosphorylate tyrosine residues on certain cytosolic proteins.

Front 42

how does Receptor serine/threonine kinases work?

Back 42

D. Receptor serine/threonine kinases

phosphorylate serine and threonine residues on certain target cytosolic proteins. Members of the TGF-β superfamily of receptors are in this category.

Front 43

how does Receptor guanylyl cyclases work?

Back 43

E. Receptor guanylyl cyclases contain a cytosolic domain that catalyzes the formation of cGMP from GTP. The receptor for B-type natriuretic peptide is one of the receptor guanylyl cyclases that has been well characterized.

Front 44

Lipophilic Molecule Binding to an Intracellular Transcription Factor/Receptor.

Back 44

e.g. Steroid hormones

Front 45

Signaling Convergence of Two Receptors

Back 45

Front 46

Cellular Regulation of

Signaling

Back 46

Hint 46

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Front 47

what does Repeated/persistent stimulation of the receptor by agonist results in?

Back 47

A.Repeated/persistent stimulation of the receptor by agonist results in phosphorylation of amino acids at the C-terminus of the receptor by protein kinase A (PKA) and/or β-adrenergic receptor kinase (βARK).

β-Arrestin blocks Gs binding, thereby decreasing adenylyl cyclase (effector) activity.

Front 48

what does Binding of β then -arrestin also lead to?

Back 48

B. Binding of β then -arrestin also leads to receptor sequestration into endosomal compartments, effectively neutralizing β-adrenergic signaling.

Front 49

what can Prolonged receptor occupation by an agonist lead to?

Back 49

C. Prolonged receptor occupation by an agonist can lead to receptor down-regulation & degradation.

Front 50

how can Cells reduce the number of receptors?

Back 50

Cells can also reduce the number of receptors by inhibiting transcription/translation..

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