Download 6]Hydrophobic Interactions

Dr. Heba Abd
ElRasheed
Lecturer of Pharmaceutical Chemistry
Faculty of Pharmacy
Cairo University
1
Drug- Receptor
Interaction
● Drug: Compound reacting with biological systems
(receptors) producing biological response.
● Receptors: are membrane bounded proteins that •
selectively bind small molecules known as ligands
that give some physiological response.
● Receptors: Protein molecules found on rigid or •
semi-rigid biologically important macromolecules as:
1- Nucleic acids [DNA, RNA].
•
2- Cell membrane.
3- Enzymes [Acetyl choline esterase, MAO, ACE….].
•
4-………etc
●The biological activity of a drug is related
to its affinity for the receptor.
(the stability of drug-receptor complex)
This stability is commonly measured by how difficult it is for the
complex to dissociate, which is measured by its Kd  the
dissociation constant for the drug receptor complex at equilibrium:
Kd = [drug] [receptor] / [drug-receptor complex].
The smaller Kd, the larger the conc of the drug-receptor complex.
Drug + Receptor
K on
K off
Drug-Receptor complex
A drug becomes inactive as soon as its concentration in the
extracellular fluids decreases.
Therapeutic aspects of
drug action
Structurally Specific Drugs
[SSD]
Structurally Non Specific
Drugs [SNSD]
Drugs producing their effects by
interaction with specific
receptors.
Their activity depends on 3D
chemical structure of the drug
which should adapt to the 3D
structure of the receptor.
Drugs producing their effects by
physical phenomenon with no
interaction with specific
receptors.
Biological activity depends on
their physical properties
E.g. Antacids, Adsorbents,
General anesthetics.
How does the Receptor
perceive the ligand?
Types of Drug-Receptor
Interactions
Reversible weak bonds
Irreversible weak bonds
1.
Ionic
(electrostatic) 1. Covalent bonds:
bonds.
 Acylation
 Phophorylation
2. Hydrogen bonds.
 Alkylation
3.
Van
der
Waals
interactions.
4. Dipole–Dipole bonds.
5. Ion-dipole bonds.
6.
Hydrophobic
interactions.
7.Charge
transfer
Weak interactions are possible only when molecular
surfaces are close and complementary (bond strength is
distance dependent).
In general, the bonds formed between a drug and receptor
are weak noncovalent interaction, so the effects produced
are reversible
Often it is desirable for the drug effect to last only a
limited time so that its action can be terminated e.g. CNS
stimulant.
However, the effect produced by a drug may be persistent
and irreversible as in case of chemotherapeutic agents as
anti-cancer.
1] Covalent bond
It is the strongest bonding force [250 Kj / mol].
It is preferred when long lasting irreversible effects
are desired.
E.g. Anti-bacterial (Chemotherapeutic agents) &
Anti-cancer drugs.
The drug effect is terminated through:
1- Catalytic cleavage of D-R linkage [by enzymes or
acid-base catalysis].
2- Metabolic turnover of receptor molecules.
1] Covalent bond
E.g. Mechlorethamine [alkylating agent], through its
Aziridinium moiety  form covalent bond with SH; COO or
PO4 anions of proteins or nucleic acids  prevent their normal
participation in cell division.
1] Covalent bond
Example: alkylation of 7-position on guanine base in each of
double strands of DNA  CROSS LINKAGE.
R
1
HN
H2N 2
O
6
O
HN
H2N
5
..
N 7
8
3
O
Nucleophilic site
4
+
N 9
DNA Srand A
R
N
CH2 CH2 Cl
CH2 CH2 Cl
HN
H2N
N
CH2 CH2 N
CH2 CH2
N
N
N
N
DNA Srand A
O
N
NH2
DNA Srand B
Cross-linked Product
+
N
N
DNA Srand B
Guanine residue in DNA
NH
2] Ionic bonds:
For protein receptors at physiologic pH (7.4)
Most drugs are either weak acids or weak bases in physiological pH
It reacts with protein receptor through
 Basic group (+ve charge: cationic sites)
e.g. guanidine group of arginine, imidazole group of histidine,
NH2 of lysine.
Acidic groups (-ve charge: anionic sites)
e.g. COOH of aspartate and glutamate.
Ionic interaction can be:
[1] effective at distance farther than required for other types of
interactions.
[2] can persist longer.
2] Ionic bonds:
The carboxylate group of the
antidepressant Pivagabine
forms an ionic bond with the
guanidino group of arginine
residue.
O
Pivagabine
O
H N
3
NH
NH
O
H N
2
3] Hydrogen bonding
It is a type of dipole-dipole interaction formed between
electronegative atoms as O,N,…. & protons attached to
electronegative atoms as NH2 or OH or COOH or carbonyl.


X
H
Hydrogen donor:
Carrying H atom.
e.g. – OH , -COOH, NH , SH
Y
Hydrogen acceptor :
Electronegative Heteroatom carrying
lone pair of electrons.
e.g. – O , -COO , N, S, Cl
3] Hydrogen bonding
 Types of H- bonds :
a) Intramolecular: Strong within the same molecule.
b) Intermolecular: Weak between different molecules.
* H- bond may highly affect the activity of drugs
O
e.g. Methyl salicylate
O
C OMe
C
OMe
H
O
OH
o-Methylsalicylate with H-bond
{ unavailable free OH gp.}
Active antirheumatic &
inactive as antibacterial
p-Methylsalicylate without H-bond
{ Available free OH gp.}
Active antibacterial &
inactive as antirheumatic
Ionic bonds
Hydrogen bonds
 20 Kj / mol.
Strong electrostatic bonding force 
between groups having opposite
charges.
Most drugs are weak acids or weak 
bases, when ionized in water  react
with the opposite charge on the
receptor:
* Cationic  e.g. NH2 gp of amino acids.
 40 Kj / mol.
Formed between electro-negative atoms as
O,N,Cl…. & protons attached to electronegative atoms.
Hydrogen bonds easily brocken  
dissociation of D-R complex.
It's formed between H-donor & H- 
acceptor:
* CH3 group  not donor not acceptor.
* Anionic  e.g. terminal COOH gp of
* OCH3, F
amino acids.
* OH, NH2  H-donor & H-acceptor.
 H-acceptor.
H
Asp
COO
-
+H
3N
Lys
Ser
H 2C
O
H
O
CH2
Ser
4] Dipole-dipole & iondipole interactions
Due to difference in electronegativity of certain atoms [e.g. O,
N..]  there's asymmetric distribution of electrons which
makes an Electronic Dipole (Permanent polarization)


C
O


C
S


C
Cl
O,N,S & Cl are


C
N

 O
carbonyl
Electronegative atoms
 OR
 O
ester
 NH2
O
amide

C
cyanide
N
4] Dipole-dipole & iondipole interactions
This dipole can form weak bond with regions of high
or low electron density such as other dipoles or ions
Ion-Dipole interaction
Dipole –Dipole interaction
● It is an electrostatic
●It is an electrostatic
attraction between a full
attraction between
partial opposite charges.
charge [ion] and a
partial charge [dipole].
Because the charge of a dipole is less than that of ion
so dipole-dipole interaction is weaker than ion-dipole
4] Dipole-dipole & iondipole interactions
 N
 C
N
Hypnotic agent
Zaleplon

O
ion-dipole

O
O
H
N
Zaleplon
N

O
N
dipole-dipole
5]Charge Transfer
Interactions
Interaction between electron deficient “electron acceptor”
and electron rich moiety “electron donor”.
The charge transfer complex is a molecular dipole-dipole
interaction.
Electron donor groups
Electron acceptor groups
● gps contain π-electrons such as alkenes,
alkynes and aromatic moieties with
electron-donating substituents or gps
that contain a pair of nonbonded
electrons such as O, N and S.
●● Electron donor [aromatic ring of
tyrosine or the carboxylate gp of
aspartate].
● gps contain electron deficient π-orbitals
such as alkenes, alkynes and aromatic
moieties with electron-withdrawing
substituent's and weakly acidic protons.
●● Electron acceptor [cysteine].
●●● Electron donor and acceptor [histadine, tryptophan and aspargine].
5]Charge Transfer
Interactions
2) The fungicide chlorothalonil & the tyrosine ring
of the receptor
CN
CN
Cl
Cl
Cl
Cl


Cl
Cl
CN
CN


Cl
Cl
chlorothalonil
Electron defficient drug
OH
OH
Tyrosine moiety
( Electron rich receptor )
6]Hydrophobic Interactions
(lipid–lipid interaction)
 In the presence of a nonpolar molecule or region of a molecule,
the surrounding water molecules orient themselves and,
therefore, are in a higher energy state than when only other
water molecules are around.
 When two nonpolar groups, such as a lipophilic group on a drug
and a nonpolar receptor group, each surrounded by ordered
water molecules, approach each other, these water molecules
become disordered in an attempt to associate with each other.
6]Hydrophobic Interactions
(lipid–lipid interaction)
•This increase in entropy, therefore, results in a decreased in the
free energy that stabilizes the drug-receptor complex.
•This stabilization is known as a hydrophobic interaction.
•The topical anaesthic butamben is described in a
hypothetical hydrophobic interaction with an isoleucine
group.
6]Hydrophobic Interactions
(lipid–lipid interaction)
e.g. : Butamben (Local anaesthetic) hydrophobic interaction
with isoleucine group of the receptor
O
H2O
H2N
O
H2N
O
Butamben
O
Isoleucine
7] Van der Waals
interactions
Formed between hydrophobic molecules [either aromatic or
aliphatic] due to the difference in electron density.
Molecules of high electron density attract area of low electron density
on other molecule (Temporary dipole).
It's due to difference in electron density in these neutral, non-polar
molecules  a transient area of  e-density & another area of  edensity  the area of  e-density on one molecule attracts another
hydrophilic area of  e-density on another molecule.
It is inversely proportional to distance. Drug
Van der waal interaction
E  1
d
Receptor
Factors affecting DrugReceptor interactions
A) Hydrophobicity (= lipophilicity)
It affects drug absorption, metabolism, binding with receptor
& its penetration to brain.
e.g. Barbiturate & Thiobarbiturate
B) Ionization
 Drugs undergo ionization according to their pKa values
 Unionized drug is non polar (lipophilic) & the ionized one
is polar (hydrophilic).
C) Steric factor
N
COOH
O
SH
1st Generation: Captopril [Capoten®]
CH3
•Disadvantages:
(1) Due to SH group  Rash and loss of taste.
(2) It is rapidly inactivated by formation of disulfide bridge 
short acting.
2nd Generation [with COOH group  Dicarboxylate] e.g.
Enalapril [Ezapril® ]
3rd Generation [with phsophinate] e.g. Fosinopril [Monopril®]
ACE (angiotensin converting enzyme) & ACEI
Glutamate [protonated]
Zn++
H
(+)
binding to Zn++
hydrophobic bond
H-bond (-)
ACE [ metallo protein enzyme ]
Drug
ionic
Concept of structure-based drug design:
•So, the requirements for the ACE inhibitor drug is :
(1) Contain anionic site [COO-]
(2) Contain H-bond forming group [C=O]
(3) Contain SH, COO- or phosphinate group to react with Zn++.
(4) Contain hydrophobic moiety [if methyl as in captopril  S isomer is more active > R]
How does a receptor change its shape?
•Hypothetical receptor may be a part of an ion channel that is closed when
neurotransmitter is absent.
•When drug bind hypothetical receptor  receptor alters its shape to obtain the
best binding interaction [conformational changes].
•Bonding forces between drug & receptor must be large enough to change the
shape of receptor BUT not so strong to make the messenger be able to leave
again.
•COO- group of the receptor is pulled closer to + ve nitrogen of the messenger
 opening of lock-gate.
•Gate remains open till the messenger detaches from the binding site.
•Finally, the receptor returns to its original shape.
O
H
O
H
H
-
O
OOC
NH2Me
H
O
H
H
-
OOC
NH2Me