Lecture 9
Last time we have talked about types of Drug – receptor interaction:
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Covalent bond
Ionic interaction
Dipole - dipole interaction
Ion - dipole interaction
Van der waals interaction
Hydrophobic interaction
Charge transfer interaction
1) Covalent bond: it is the strongest interaction
– It has advantages and disadvantages depending on the medical
situation.
*e.g. where the use of covalent bond is an advantage:
Anticancer, phsycotoxic drugs, anti-bacterial, anti-viral [anti microbial in
general].
*Disadvantage:
- Irreversible, strong bond => may result in toxicity
- Main problem or disadvantage for covalently bound drugs is activity
regenerate (get back to the synthesis of the receptor) => this may be
advantage in the case of antimicrobial agent while it will be a
disadvantage when the receptor is essential for biological process.
- Protein when covalent modification (a very common side effect for
drugs which have covalent mechanism of action) e.g. penicillin
- The most common serious side effect of penicillin is the allergy ,
because the protein may become immunogenic , the body may act
against it as allergen even if it was an endogenous protein.
If our body didn't recognize the protein, and if this protein is a normal
protein found in our body, with covalent modification (genetics and
other factors) the body may identify them as antigen => form antibodies
and make immune reaction.
**" Usually drugs that have covalent mechanism of action make allergic
reaction or immune response"
2) Ionic Interaction: second strongest interaction
strength (difference in enthalpy) = around (-5)
3) Dipole – Dipole interaction: Permanent partial charge (- δ, + δ)
Must have an electronegative ion and a neutral atom
** Hydrogen bond is a special case from the Dipole – Dipole interaction
-Hydrogen bond (-3 to -5) kcal /mol
-H-bond is important to maintain the structure of proteins, DNA…
- Intermolecular H-bond: 2 functional groups make H-bond within the
same molecule.
- Intermolecular H-bond: interaction between different molecules.
*Intramolecular interaction makes conformational bias (make one shape
more favored by the molecule), it may also decrease the interaction with
the receptor (it is less specific)
-They are important, they give the: α- helix, β- helix sheets and double
helix DNA, according to the H-bond shape and angle.
** H-Bond is a vector Bond => must assign amount and direction
for e.g. if the H-bond direction change it will be weaker.
4) Van der waals interaction:
- Between non-polar groups
- It is a temporary induced charge
- Temporary, non symmetrical distribution of electron density results in
temporary polarization.
** Difference between Van der waals interaction and hydrophobic
interaction:
Van der waals interaction is a temporary induced dipole – dipole
interaction
Ions are in continuous movement so if grouped in one side they will
make a – δ charge and on the other side + δ => this will induce a
temporary transient polarization in the adjacent molecules so make
interaction between them .
5) Hydrophobic interaction:
(-0.7 kCal/mol) per methyl group.
-No H2O
-No change ( +Ve , -Ve)
-All the interactions depend on the Enthalpy Changes of energy EXCEPT
the hydrophobic interaction , the only interaction affecting the intropy.
If we have two hydrophobic groups and both are solvated they will be in
a high energy status , and when they bind to each other they will
decrease energy because of the increased freedom of H2O molecules.
That's why it is a very important interaction especially when making
antagonist or inhibitor , because it have additive effect and because it is
intropy induced.
*What's the difference between entropy induced and enthalpy induced?
- the H-bond  Make enthalpy : I must pay energy to break the bond
and free the molecule, so it is not favored
WHILE Hydrophobic  increased the entropy in the system, so this will
push the interaction to happen.
So the advantages of the hydrophobic interaction that it increases the
entropy in a system, & it make freedom for H2O molecules. [more H2O
molecules free  system is more entropy driven ].
6)Charge Transfer
depends generally on π electrons (-1 to -7 kCal/mol )
-Rich in electrons e.g. Aromatic system.
- Atoms that have unbound electrons, unshared pair of electrons
-double bonds  are conjugated, making resonance:
are called π electrons [ They have more freedom to move ]
- the interaction between two aromatic systems is called π-π Stacking
[one will be e- donor and the other will be e- acceptor ].
-Some amino acids may act as Donor or acceptor e.g. : Tyrosine (R-
group is phenol ), phenylalanine ( R - benzene group ) , Aspartate ( Rgroup : carboxyl )
Some amino acids are only acceptors e.g. cystein (R – group : SH )
Note:
It is important to know each part and each F.g in the structure what type
of interaction they will make.
Donor and acceptor Hystidene , aspargine ( R- amide of aspartate )
** Study for the Exam: names of aromatic rings
also the structure of the rings(in the slide ) are for memorize.
e.g.
N
H
N
N
Types of interactions for each F. g :
- Butyl :
- Hydrophobic
- Van der waals
- Ether :
- H-Bond acceptor
- Dipole – dipole
- Ion – dipole
- Pyridine :
- HBA
- π- π stacking ( charge taransfere)
- Ion – dipole
- π Cation
- Hydrophobic
- Van der waals
- Benzene:
- π- π stacking (charge transfer)
- Ion - dipole
- Cation ( π Cation )
- Hydrophobic
- Van der waals
- C=o
- Dipole – dipole
- Ion – dipole
- Van der waals
- Hydrophobic
- C=o
- H-bond
- Dipole – dipole
- Ion – dipole
- NH
- HBA
- HBD
- Dipole – dipole
- Not ionizable
- C=C
- Van der waals
- Hydrophobic
- N (3º amine)
- Ionization (Ionic Bond)
- HBA
- Dipole – dipole
- Ion – Dipole
- The two Ethyl :
- Van der waals
- Hydrophobic
So far we have talked about the types of interactions , the features of
the receptors
Now we will start to make analysis, understand how the response will
occur after interaction.
Molecules => interact with certain receptor => make biological activity.
** Types of biological activity / action of the drug on the receptor:
1) Antagonist : opposite effect , stop the effect of the ligand
2) Agonist : same biological activity of the biological ligand
** what make a chemical compound works as agonist and other
compounds works as antagonist ??
Maybe depending on the structure , conformation & interaction
That certain interaction makes activity and other interactions make
block to the activity.
** Competitive Vs non- competitive:
Competitive : bind to the same site where the ligand bind ,while th
non-competitive "alosteric " bind to another site on the receptor =>
make conformational changes in the => so the ligand can't bind to the
receptor .
In order to understand we need to define some terms
Affinity: the ability of the molecule to bind to the receptor , depending
on shape , stereochemistry and interactions
" Affinity doesn't mean that ther must be an effect … only that the
molecule bind to the receptor "
- After affinity  biological action
Action activity
Efficacy
 Potency
Efficacy: Related to the response (ability of the drug to make response)
Nothing to do with the dose, it's about there is action or no action
Potency: Dose response relationship (related to the dose)
High dose  low potency
Low dose  high potency
Steps of drug – molecule interaction:
-according to the induced fit theory :
1) Conformational changes
2) Affinity
3) Efficacy
- according to the occupancy theory:
1) Affinity
2) Efficacy
** We need conformational changes for association and dissociation
from the target
** Dose- Response relationship: ( to determine Potency )
** It is difficult to deal with the hyperbolic function because the slope is
variable.
so we take the Log : Convert the hyperbolic to sigmoidal.
Differentiation  Inflection point.
Around the inflection point we'll have a linear relationship.
 We can use it to find the slope .
as a standard we use EC50
EC50 : is the concentration which give us 50% of the maximum activity .
ALSO:
IC50 : Concentration which give us 50% inhibition.
LD50 : Lethal dose for 50%
**Why we use the term 50%NOT 100% ??
Because we will reach 100% at infinity ∞
So practically no way that any system can reach 100% Because we need
infinite ∞ time to reach 100% .
Done by: Rasha Khair al-deen Bsisu