2.3 drug design Flashcards
(38 cards)
What is the goal of structure-based drug design (SBDD)?
To design small molecules that regulate protein function based on structural insight.
What are the main drug target classes?
Receptors, ion channels, enzymes, and carrier molecules.
How do drugs typically interact with targets?
They bind to active or regulatory sites to modulate function.
What is required for rational drug design?
Knowledge of the 3D structure of the target and the ligand-binding interactions.
What are the steps in SBDD?
1) Target identification & characterisation, 2) Hit identification, 3) Hit characterisation, 4) Hit modification.
What methods are used for hit identification?
Known ligands, high-throughput screening (HTS), docking (computational HTS), de novo fragment-based design.
What is hit characterisation?
Functional assays and studies of how hits interact with the protein.
What guides hit modification?
Structure–activity relationship (SAR) and ligand–protein structural data.
What features of protein structure aid SBDD?
High-resolution 3D structures, surface charge, and defined binding pockets.
What does red and blue coloring indicate on surface charge maps?
Red = negative charge, Blue = positive charge.
What determines high specificity in small-molecule drugs?
Complementary shape and charge, and selective binding to specific protein conformations.
What is BCR-Abl?
A fusion protein from the Philadelphia chromosome translocation in CML, with constitutive kinase activity.
Why is BCR-Abl a good drug target?
It’s disease-causing, has a conserved kinase domain, and a well-characterised binding site.
How does imatinib interact with BCR-Abl?
It binds the ATP-binding site in the inactive conformation, forming 21 stabilising contacts.
Why is imatinib highly specific despite being ATP-competitive?
It binds only the inactive form of Abl, which is not conserved across all kinases.
What causes resistance to imatinib?
Mutations in the ATP-binding pocket, especially at key contact points.
What second-generation inhibitor was designed to overcome this?
Dasatinib.
What mutation makes both imatinib and dasatinib ineffective?
T315I gatekeeper mutation.
How does ponatinib overcome resistance?
It does not rely on the hydrogen bond to the threonine residue at position 315.
Why is HIV-1 protease a good drug target?
It’s essential for viral maturation, with a well-characterised active site and structure.
What is the structure of HIV-1 protease?
A dimer with an active site formed between the two monomers, containing a catalytic aspartate dyad.
How was the first inhibitor (saquinavir) designed?
Based on peptide analogues; a hydroxyethylene bond replaced the labile peptide bond.
Why did saquinavir need improvement?
It had poor bioavailability.
What strategy improved on saquinavir?
Optimised interactions with the protein backbone, minimized side-chain dependence.
