Drug Targets Flashcards
What are the non-covalent interactions that influence protein structure?
Hydrogen bonding, salt bridge formation (electrostatic interactions), hydrophobic effects, aromatic stacking
How do hydrophobic effects and aromatic stacking interactions arise?
Hydrophobic effects arise from solvent entropy, aromatic stacking due to polarisation of aromatic rings, generally edge-to-face interactions in proteins.
What is competitive enzyme inhibition?
Inhibitor and substrate compete for the same active site.
What is non-competitive enzyme inhibition?
Inhibitor binds non-covalently to sites away from the active site and impacts enzyme conformation, affecting activity.
What is uncompetitive enzyme inhibition?
Inhibitor binds to the enzyme-substrate complex.
What is a suicide inhibitor?
Permanent covalent link formed to enzyme, generally in active site.
What are G proteins used for?
G-proteins used to transfer information across cell through generation of cAMP.
How do G proteins work?
Ligand binds to GPCRs leading to formation of G-a-GTP complex, releasing GDP and undergoing dissociation. G-a-GTP binds to adenylate cyclase (AC). This leads to the generation of cAMP, which activates protein kinase A, which then catalyses phosphorylation of wide range of proteins. Moderated response as G-a slowly hydrolyses GTP back to GDP.
How do receptor tyrosine kinases work?
Extra-cellular ligand binding domain interacts with polypeptide ligand. After ligand binding, intra-cellular kinase domain is phosphorylated, then available for transfer to multiple substrates. Signal amplification achieved as ligand dissociation does not turn off signal.
How do secondary messengers get involved in signal transduction?
Binding of a ligand to a receptor leads to activation of an effector. This promotes formation of a secondary messenger. Secondary messenger interacts with key targets to induce a response.
How does signal amplification arise?
Secondary messengers change activity of an enzyme, which activates other enzymes. For each enzyme, multiple copies of next effector produced, so from a single receptor binding event, large response formed = signal amplification.
What is an ion channel?
Allow selective movement of ions across cell membrane in order to maintain unequal ion concentrations inside and outside the cell.
Why are calcium channels important drug targets?
Calcium channels in particular involved in muscle cells (e.g. heart) and lots of other pathways! [Ca2+] carefully regulated in cells, low due to export and maintenance of internal stores. Drugs targeting calcium channels used to treat angina (restricted blood flow to parts of the heart).
