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Relationship (QSAR)
As shown we can estimate the relative solubility of drugs on the
basis of the structure features.
However, there is a relationship between the quantity of the drug
that binds to the active site and its structure and thus, the
biological activity.
This relationship is called quantitative structure activity
relationship (QSAR).
QSAR can be used:
Definitions:
Acid: An organic compound containing a functional group that can donate a
proton (H+)
Base: An organic compound that contains a functional group that can accept
a H+
2
O
R
C
O
H2O
O-
H3O+
SO2 NH2
H2O
H2O
R
N H
H3O
Phenol
H2O
N-
+ H3O+
Imide
NH3 +
NH2
H2O
H3O+
O-
Sulfonamide
Carboxylic acid
O
SO2 NH-
H3O+
Anilinium cation
3
R N
R
H3O+
R N+ H+ H2O
R
Aliphatic amines
H3O+
Heteroaromatic amines
H3O+
H2O
Aromatic amines
+
N+
R
H2O
N
Pyridine
N
H
NH
Imidazole
Piperidine
4
E.g. Ionization of weak acid (e.g. acetic acid, pka =4.76) is as follows:
NH4+ + H2O
NH3 + H3O+
5
INCREASEING ACIDITY
ACIDS
INCREASING BASICITY
ACIDITY pKa
NAME
ACID
Sulfonic acid
RSO3H
4.5
Carboxylic acid
RCOOH
6-9
Aromatic sulfonamide
ArSO2NHR
8-11
Phenol
ArOH
8-10
R
Imide
N H
R
O
NAME
ACID
3-4
Aliphatic amines
9-13
Aromatic amines
ArNH2
4-12
Heterocyclic amines
Pyridine, piperidine,
imidazole
7
Carboxylic acids
O
R C
Sulfonamides
O
H2O
O H
R C
H3O
H3O
H2O
H2O
ArSO 2 NHR
R SO2 NH
R
N H
H3O
H2O
+ H3O+
Phenols
Imides
II-Bases
R
R N
R
H3O+
R
R N+ H+ H2O
R
Aliphatic amines
NH3 +
NH2
H3O+
H2O
Aromatic amines
H3O+
Heteroaromatic amines
H2O
+ NaOH
HCl
RCOO Na
+
H2O
R3NH Cl
11
Drug-receptor Interaction
Receptor is the site in the biological system where the drug exerts its
characteristic effects or where the drug acts.
Receptors have an important regulatory function in the target organ or
tissue.
Most drugs act by combining with receptor in the biological system
(specific drugs).
1-cholinergic drugs interacts with acetylcholine receptors.
2-synthetic corticosteroids bind to the same receptor as cortisone and
hydrocortisone
3-non steroidal anti inflammatory drugs inhibit cyclooxygenase enzyme
that will inhibit the formation of prostaglandins which will lead to
inflammation symptoms.
Non-specific drugs do not act upon receptors.
The receptor substance is considered mostly to be a cellular constituent.
Recent studies, however, indicate that the receptors are proteins or 12
Drug-receptor Interaction
The ability of a drug to get bound to a receptor is termed as the affinity of
the drug for the receptor.
The receptors are also dynamic in nature and have a special chemical
affinity and structural requirements for the drug. Thus, affinity
represents kinetic constants that relate to the drug and the receptor.
The drug elicits a pharmacological response after its interaction with
the receptor.
A given drug may act on more than one receptor differing both in
function and in binding characteristics (non-selective drugs).
There are also many factors effect changes in receptor concentration
and/or affinity.
A drug, which initiates a pharmacological action after combining with
the receptor, is termed agonist.
Drugs which binds to the receptors but are not capable of eliciting a
pharmacological response produce receptor blockage, these
13
compounds are termed antagonists.
14
15
CH3
H
OH
CH3
H
CH3
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)
HO
OH
Cis-die thylstilbestrol
HO
Trans -die thylstilbestrol
17
(CH3) 3
H
H
OAc
Trans
N
H
(CH3) 3
H
OAc
H
Gauche
Conformations of acetylcholine
18
N= N+ O) ;
19
CH3
CH2 CH3
CHO CH2 CH2
CH3
CH2 CH3
Compound A has twice the activity of C, and many times greater than B
20