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Medicinal chemistry
Third stage
Lecture 1
Drug Design
Dr. Narmin Hussen
B.Sc. In Pharmacy
M.Sc. In Ph.chemistry
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Content
Medicinal chemistry
 Drug design
 Drug distribution
 Protein binding

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Medicinal chemistry

Medicinal chemistry is the chemistry discipline
concerned with the design, development and synthesis of
pharmaceutical drugs.
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Drug design
Drug

A drug is a chemical substant ,that can affect living
processes , absorbed via a different route of
administration causes a physiological change in the body.
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Drug Design
 The
study of the shape of molecules in order to
determine how they will bind receptors on cell
or combine with other molecules.
 One
of the goals is to design drugs that will
interact with receptors at specific sites.
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There are several ways to do this:
1.
Altering the molecule, which in turn , can change the
biodistribution.
Biodistribution can be altered by
a. Changing the drugs solubility.
b. Enhancing its ability to resist being metabolized (
usually in liver).
c. Altering the formulation or physical characteristics of
the drug.
d. Changing the rout of administration.
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2- Increasing specificity for the target receptor that will
produce the desired pharmacological response while
decreasing the affinity for undesired receptors that produce
adverse response.
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Stages of drug metabolism
 Absorption- drug gets into bloodstream



Distribution - gets to site of action
Metabolism - is “changed” so that it can be excreted
Elimination - leaves the body
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Drug distribution
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Factors Affecting Drug Distribution
1. Tissue Permeability of the drug .
a.
Physiochemical properties of drugs like ( molecular size
, Pka , Partition coefficient ).
b.
Physiological barriers to diffusion drug.
2. Organ/tissue Size and Perfusion Rate.
3. Binding of Drugs to Tissue Components.
4- Miscellaneous factors
age , pregnancy , diet , obesity ,disease and drug
interaction).
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Rate of absorption

I.V ( has no absorption)
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Oral administration ?
Several factors affect the ability of the drug to be
dissolved :
 Chemical structure
 Particle size and surface area
 Crystal form
 Type of tablet coating
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Example
Mesalamine



Not effective orally
Metabolized to inactive form.
Used in the treatment of ulcerative colitis.
Olsalazine
This drug is adimer of pharmacologically active mesalamine.
 In active form (prodrug)
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Chloramphenicol




Water solube (2.5mg/ mL)
Bitterness
The palmitic acid moiety is added as an ester of
chloramphenicol primary alcohol.
Reduce water solubility (1.05 mg / mL).
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Enalaprilic acid

Poor absorbed from the gastrointestinal tract.
Enalapril is the ethyl ester of enalapric acid , an active inhibitor
of ACE .
 The ester prodrug is much more rapidly absorbed orally than
the pharmacologically active carboxylic acid.

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Parenteral administration
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Methylprednisolone
Both sodium succinate and acetate esters are
hydrolyzed to the active methylprednisolone
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Etertinate and Acitretin
Two drugs based on the retinoic acid .
 Alter biodistribution and biological half life .
 Used systemically to treat psoriasis.
 Both drugs are potentially teratogenic.

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Protein binding
There are many types of proteins in the blood plasma(
ex. albumin).
 These proteins bind to different types of drugs.
 Drugs that are protein bound are not able to activate
receptors unless they are free.
 These proteins act like a sponge on many drugs ,not
freeing the drug until the proteins are saturated.

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
After adding 6 units of drug A , all the drug is protein
bound, there is no drug to activate receptors.

After adding 12 units of drug A, all the protein binding
sites are saturated.
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
Now that protein binding sites are saturated, adding the
drug results in the free drug to activate receptors.
Stopping or starting a drug that binds to plasma protein
changes the free drug levels of other protein bound drugs.
 Now that protein binding sites are saturated, adding the
drug B results in higher levels of free drug A.

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Example
 A person was admitted to the hospital for surgery. A
person took drug A( warfarin) as an anticoagulant (blood
thinner) and drug B (phenytoin) as an anticonvulsant.
Both drugs are highly plasma protein binding drugs.
 Three days before surgery the warfarin was stopped

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Because warfarin is protein bound and stopped, this left
binding sites available for phenytoin.
 This increases the effective concentration of warfarin at
receptor , leading to an increased prothrombin time and
potential hemorrhage.


The extra binding sites bind to free drug B, making it
unable to activate drug B (phenytoin) receptors.
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Summary
Factors Affecting Drug Distribution .
 Several factors affect the ability of the drug to dissolve.
 Prodrug
 Protein binding

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Home work
1.
What is blood-brain barrier ? Why some drugs by passes
it and some others are not?
2.
Compare between the following:
passive and active diffusion through the mucosal cells.
Lipid bilayer and aqueous layer of cell membrane.
A.
B.
3.
Why some drugs are prolong duration of action ? Give an
example.
4.
What is tissue depots? Explain your answer by giving
some examples
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