Lecture 22 Flashcards
Covalent Drugs
1
Q
Drugs + Binding
A
- Drugs bind to receptors or inhibit enzymes usually
- Usually strong/specific bonds need MULTIPLE, WEAKER (non-covalent) interactions
- Multiple, weakly interacting groups held in place by a scaffold to have them interact optimally with receptor(s)
2
Q
Binding Types
A
- Covalent (rare)
- Ionic
- Hydrogen
- Hydrophobic
Decreases in strength as list descends
3
Q
Covalent Drugs
A
- Covalent bond is made between drug or metabolite and target (usually protein).
- Molecular orbital is formed between the drug and metabolite
- LOTS of different linker chemistries, most involved drug electrophile reacting with neutrophile (thiol, amine, DNA base)
4
Q
Covalent Drugs Advantages
A
- Good for antibiotics and other reactions where prolonged, usually irreversible reactions, are beneficial.
- Longer half lives
- High compliance
- Longer time of action
- Suppresses enzyme with no breakthrough
- Higher ligand efficacy
- Can be more selective by utilizing covalent and non-covalent bonding
- Can target any biomolecule
- Can take out entire receptor system.
5
Q
Covalent Drug Disadvantages
A
- Toxicity from hapten formation
- Potential for DNA damage and mutagenesis
- PK/PD studies not possible since effects are disconnected from plasma levels
- Can’t reverse in an overdose situation, just supportive medication until it works itself out.
6
Q
Targeting
A
- Ideally only want reaction with target and not broadly reactive with all cell proteins
- Usually achieved by having some normal, receptor-ligand interactions to drive specificity like a non-covalent drug
- Sometimes other (omeprazole and pH) or no targetting occurs (certain chemotherapies)
7
Q
Warheads
A
- Group on receptor that creates the covalent bond
- Lots of variation in structure and mechanism
- All held in target site, not free
8
Q
1-Phenoxybenzamine
A
- Antihypertensive targetting alpha receptors
- Shuts down receptor
- Used in phaechromocytoma - agonist releasing tumor of adrenal gland that causes very high blood pressure
- high levels of catecholamines can’t be inhibited without suffering side effects from high doses of alpha or beta blockers
- Some similarities to ephedrine which helps give rise to some of its specificity
9
Q
Plavix
A
- Prodrug activated mostly by CYP2C19 to “arm” the warhead
- Makes a reactive thiol when metabolized that irreversible reacts with receptor PCY12 on platelets
- Additional targetting on rest of molecule as well
- Metabolized by oxidation of aromatic carbon
10
Q
PPI
A
- 1st = omeprazole
- Irreversible inhibitor of acid secretion in stomach with a half life of effect of >24 hours
- Targetting feature: acid sensitive site on molecule
- Intestine»_space; Blood»_space; Parietal cell»_space; Lumen, pH 1»_space; Activation»_space; Reacts with thiols that are ATPases
11
Q
DNA Agents
A
- Alkylating agents and cisplastin
- No major targetting other than mainly react with nucleic acids
- React to crosslink DNA
12
Q
Modern Trends
A
- Covalent by design, not accident
- Stronger, non-covalent targetting to drive specificity
- Less reactive warheads to lower off-target reactions
- Avoid metabolic warhead arming by P450s
- Develop for severe conditions without better options to tolerate some toxicity
