Chapter 6 Drug binding Interactions Flashcards
Characteristics of covalent bonds:
-The strongest bond between a target and a drug
-highly therapeutic effective (target is modified forever)
-long duration
-not easily reversible
What is the difference between Zantac (H2 receptor antagonist) and Nexium (PP inhibitor)?
-Zantac is an antagonist and builds non-covalent bonds (hydrogen bonds,..) and modifies the target temporarily
-> works faster, it is reversible but doesn’t last long
-Nexium binds covalently
-> takes longer to work (no relief for 24h), hard to reverse, last longer due to covalent bonds
-another example of a covalent-bonded drug is Clopidogrel (anti-platelet) it would take a lot to reverse the bond to decrease the risk of bleeding (Offtopic: CYP-dependent, patients are screened for their CYP)
OR
Zidovudine: binds covalently to HIV, which is preferred bc it deactivates the virus irreversibly
-> Addition of Phosphate group (3rd way of covalent bonding)
What is Alkylation?
COVALENT
-Covalent bonding driven by a bond to a carbon ion
-Example Cisplatin: forms a covalent bond with DNA
How it works: the target itself is attacking the drug -> the target is nucleophilic and the drug is highly electrophile
Example in nitrogen mustard: the Cl(-) leaves the drug, and makes it more reactive (electrophilic (+) charged, -> forms a bond to the carbon of the base
What makes the base nucleophilic?? Why does the base want to bind with the target??
What is Acylation?
COVALENT
-Nucleophilic atom/functional group on target attacks
ester !!, carbonyl, lactone, amide, lactam, of carbamate on drug
molecule
-Example: protein with Ser residue -> Nucleophilic target (with Serin) attacks electrophilic drug (carbonyl, lactam ring -> it is reactive bc the molecule are close and they do not like that)
Phosphorylation:
COVALENT
-Addition of phosphate to the drug structure
-often in antiviral drugs
-Example: Zidovudine
Why are covalent bonds avoided when designing drug structures?
-Because of the risk of toxicity (Noncovalent bounded drugs can be kicked off by adding another drug that is stronger noncovalent binding)
-But in case of infections and cancer as a target we want covalent bonding to terminate it
Characteristics of non-covalent-bonds:
-Weak individually but strong in numbers
-the drug is held in the drug-target-complex by multiple non-covalent-bonds (hydrogen, ionic interactions, hydrophobic interactions)
-it is reversible
-represented by affinity ratio -> bound drug : unbound drug
-> a drug with higher affinity can be used to bind to opioid receptors, naloxone (antidote) has a higher affinity than oxycodone
Ionic drug interaction (ION-ION)
NON COVALENT
-strongest non-covalent bond
-between (+) and (-) charged molecules -> ACID and BASE
-pKa dependent bc if the molecule doesn’t get ionized, we will not see an ionic interaction
-> f.e. a phenol (ring with OH) is a weak acid that is very hard to ionize, even though it is an acid we will not see an ionic bond
-all basic and acidic amino acids are ionized at physiological pH
What is the difference between an ionic interaction and an electrophilic - nucleophilic attack?
-Ionic bonds are between (+) and (-) charged species without sharing electrons -> weak, non-covalent
-a nucleophile is an atom that needs that positivity (nucleus-loving) to equalize -> so it attacks an atom that has the positivity and shares electrons with it -> strong, covalent
Dipole Interactions
NON COVALENT
(most common non-covalent bond)
-drug-target interaction between 2 polar functional groups
-it can be ION-DIPOLE (only one of the interacting groups is charged and the other one is polar like OH or acid COOH??)
or DIPOLE-DIPOLE (both are uncharged, can also be between uncharged acids and bases -> so I think below or above physiological pH )
Hydrogen bonds
NON COVALENT
-is a type of DIPOLE interaction -> so one reactant has a dipole within a bond including a HYDROGEN (always less electronegative)
Hydrophobic Interactions
NON COVALENT
-occur between non-polar functional groups
-referred to as Van-der-Waals force (things that are in close proximity, not the only type of VdW force)
-Example: Phenyl stacking between 2 phenyl rings (rings without substitutes on them -> 1 ring on the drug, 1 ring on target -> delocalized electrons cause electron-sharing force)
-it is not an attracting force (like (+) to (-) or dipoles), its just between groups that want to prevent interaction with water
-> REPULSION of water causes the interaction of non-polar drug and non-polar target
Complexation AND Chelation
NON COVALENT
COMPLEXATION:
-Non-covalent bonds between a metal-ion or more than one metal and one SINGLE functional group
f.e.: Captopril (ACE-Inhibitor) with Serine binds Zinc, which is part of the target (ACE)
-coordinated-covalent bond (hybrid between covalent and non-covalent bond), it contains partially electron-sharing
CHELATION:
-there is more than one electron-donating group on the drug that interacts with metal-ions
f.e.: Tetracycline targets bacterial ribosomes, bacterial cells take up Mg -> Tetracycline chelates Mg and thereby enters the bacterial cell
Which functional group is most capable of forming a bond with Zinc? And what is an alternative?
Sulfthiol (SH)
Switch from SH to COOH:
ACE Inhibitor: bc SH binds very well to Zn, patients with high sensitivity to sulfur have taste reaction or dermatologic side-effects
