Receptors as drug targets

Question 1

Ideal drug

Answer 1

Small molecule featuring high potency,selectivity, few adverse effects, low production costs and administration in a single daily oral dose.

Question 2

Why are GPCRs sucessful drug targets?

Answer 2

Largest family of related proteins known to exist
Multiple subtypes tupically with distinct patterns of expression.
Often involved in disease pathology.
Potential for specificity of targetting.
Ligand/drug binding sites accessible at cell surface.
Multiple ways to manipulate GPCR activity (agonists,antagonists,alosteric modulators)

Question 3

Classical pharmacological approach to drug discovery

Answer 3

Function (behavioural/pharmacological effect)
Drug (determine pharma of response and develop selective agonists/antagonists)
Gene (receptor purification and cloning)
Medicine

Question 4

Discovery of chemokine receptors as HIV co-receptors on macrophages and T-cells

Answer 4

Membrane protein CD4 found to be necessary but not sufficient for HIV-1 infection of Tcells monocytes and macrophages.
T-trophic HIV-1 strains infects only T cells
M-trophic HIV-1 strains only infects monocytes/macrophages.
Dual trophic HIV-1 strains infects both.
All strains interact equally with CD4.
HIV-1 co-receptor absencse or antibody blockade of GPCRs nlocked HIV-1 entry into CD4 cells.

Question 5

CXCR4 and CCR5

Answer 5

HIV co-receptors on macrophages and T cells.
CD4 interaction on T cells or monocytes with HIV protein gp120 allows gp120 to bind theres co-receptors.
Binding energy alters conformation of complex and exposes the fusion peptide gp41. Membrane fusion causes viral entry. Synthesis of New viral particles precedes their release and destruction of infected cell.
Synthetic agonists to promote desensitisation or antagonists to block binding sites of theres receptors may be good anti-HIV drugs

Question 6

Reverse pharmacological approach to drug discovery

Answer 6

Gene ( bioinformatics/ date mining, expression profiling)
Drug (receptor cloning and expression)
Function (functional assays)
Medicine (agonist/antagonist)

Question 7

Pathophysiological roles of angiogenesis

Answer 7

Tumour growth and metastasis
Psoriasis
Endometriosis
Diabetic retinopathy
Rheumatoid arthritis

Question 8

Inhibitors of enhanced angiogenesis

Answer 8

PDGF receptor inhibitors
VEGF receptor inhibitors
Examples
Sunitunib - potent ATP competitive inhibitor of PDGF and VEGF receptor Tyrosine kinase activity. Targetted.
Sorafenib - inhibitor of multiple protein kinases, inhibits VEGF kinase activity, PDGF kinase activity, c-KIT kinase activity, and Raf kinases.