Introduction to Medicinal Chemistry
Dr. Soha Telfah
Assistant Professor,
Pharmaceutical Medicinal Chemistry,
Faculty of Pharmacy,
Philadelphia University-Jordan
Learning Outcomes
At the end of this lesson students will be able to
Outline the basic concepts of Medicinal Chemistry.
Describe about drug, targets, roles of medicinal
chemistry in drug design and discovery.
Describe the basic concepts of pharmacokinetics and
pharmacodynamics.
Explain the fundamentals of receptors and drug-receptor
interactions.
Introduction to Medicinal Chemistry
Medicinal Chemistry is the science that deals with
the design and development and modification of
pharmaceutical agents that has a desired biological
effect on human body and other living systems.
Drug is a compound that interact with a biological
target to produce a biological response:-
Biological target: Human, bacteria, fungi,
….(COX 1 COX 2: examples)
Biological response: desired or undesired
(side effect).
Medicinal chemists concern about the synthesis of
new molecules to investigate the relationships
between the chemical structure of these compounds
and their biological activities. SAR
CADD: computer aided drug design
Medicinal chemistry also involves isolation of
compounds from natural sources.
Relationship with phytochemistry
Ideal drug must be:-
Not toxic
Effective and potent
Selective
Easily administered
Cheap
(example : Paracetamol)
Penicillin: one of the safest and most active
antibiotics……BUT….. Resistance developed to most
of them.
Morphine: a very effective pain killer….. BUT…. May
cause tolerance, addiction and respiratory
depression.
Heroin: the best pain killer we know….BUT….
addiction developed (still used in terminal cancer).
Poisons can be drugs at lower doses:-
Arsenicals: very toxic but used as antiprotozoal
agents.
Tubocurarine:- It used as muscle relaxant.
Arrow poison
Drug might be harmful at higher doses:
Therapeutic index =
it is the ratio of the dose leads
to toxic effect in 50% of cases to that leads to
therapeutic effect in 50% of the cases.
high dose
Drug poison
low dose
Large therapeutic index…… safer drug.
narrow therapeutic index…… more toxic drug.
(digoxin, warfarin)
Selective Toxicity
Selective Drugs: that show toxicity against
abnormal cells without affecting normal cells.
Ex: anticancer drug ( low selectivity: still have side
effect)
Degrees of selectivity:-
No effect on normal host cells (ex: Penecillin).
Killing certain microbial strain without affecting
others (especially normal flora).
Targeting certain metabolic pathway without
affecting others. : folic acid pathway (vitamin B9)
Drug Targets
They are macromolecules (receptors,
enzymes, DNA or transport proteins).
Drugs interact and bind to the binding sites
through intermolecular bonds (ionic, H-bonds,
van Der Waals, dipole-dipole and hydrophobic).
Sterically (size, shape and orientation) and
electronically binding
The bonds mainly are weak, therefore in most of
the cases this binding is reversible.
Interactions involved between
drug and receptor
Covalent bonding Irreversible bond
Anticancer, antimicrobial PPI
Ionic (electrostatic)
full opposite charges
Dipole-dipole interaction
Partial opposite
H-bonding
Partial negative with polarised hydrogen Reversible bonds
Hydrophobic interaction
Entropy not enthalpy
Van der Waals forces
Transient opposite charges
Hydrophobic
Ionic bonding interaction
Dipole-dipole
interaction O N
H
OH
Aromatic
interaction or
pi –pi stacking
HN
O
Hydrogen bonding
H
X
Practolol inside the adrenergic B-receptor
N
OH Cl
HO N
O O
O
O Cl
Hyoscine Chlorambucil (Leukeran)
Anti-cholinergic for chronic leukemia
O O
H2N Pt O
NH2
Oxaliplatin
Human FAS
fatty acid synthase
Orlistat
Pharmacokinetics
Pharmacokinetics: How the drug distribute
and reach its target (AD ME) and what will
happen to the drug.
(Drug -receptor interaction) pharmacodynamics
Pharmacokinetics – what the body does to the
drug.
How does drug get into the body? absobrption
How long does it take to exert its action? Onset of
action
How long does it stay in the body? Duration of action
“pt compliance “
Where does it go to in the body? distribution
Is it metabolised to another form? Metabolism
Inactive. metabolism Active (Prodrug)
The [plasma drug] -time curve after
drug administration
ADME Acronym
Pharmacokinetics
Which route?
Which formulation? Drug administered First pass effect
Metabolic
Drug absorbed
inactivation
Which barriers to cross? Passive diffusion?
Gut, skin, lungs? Active transport? By pumps, ex: proton pump
Stability at the site of absorption? Blood-brain barrier penetration?
Pool of non-available available
Drug in the tissues Drug in the plasma Excretion
•Plasma-protein
binding? Example zwitterion
• Electrostatic charge like penicillins
•Tissue-protein Decrease
binding? Drug at the site
•Fat storage?bone?
of action
Pharmacokinetics
Drug administration: How is the drug to be
formulated? If as an injection, is it soluble in
aqueous solution? If as a tablet, will it dissolve
when released in the gut?
Tablet disintegration dissolution absoprption
Drug absorption: can the drug pass through the
barrier membranes in the GIT? Can it pass through
the skin barriers? These barriers are made up in a
large part by lipids, so the drug must be sufficiently
lipophilic/ unionized to diffuse through them.
Membranes have phospholipids bilayer that act as
barriers to the movement of drugs within the body
Polar head: phosphate (-)
Non-polar tail
Pharmacokinetics
Drug metabolism: Metabolism increases the
water solubility of drugs by enzymatically
introducing polar functional groups so that
they can be excreted. What is the chemistry of
the drug? How fast is it inactivated? Is it
converted into more active or even toxic
components?
Drug excretion: Kidney excretes water-soluble
metabolites and the ionized forms of drugs.
*
Pharmacodynamics
Pharmacodynamics: How the drug interacts
with its target.
Pharmacodynamics: What the drug does to
the body.
What is the therapeutic effect of the drug?
How does it exert its effect? Ex: Signal transduction
How does the drug interact with the
target?
Can the effect be modified? SAR
Pharmacodynamics
More than 90% of drugs have biological targets to bind with
in order to exert their pharmacological effects.
Biological targets: are endogenous macromolecules including
DNA, RNA, enzymes, receptors, membrane proteins, etc…
The nature of drug-receptor binding
Either reversible or irreversible.
Reversible binding means that the drug-target
complex will dissociate to release the free functioning
target.
Irreversible binding means permanently blocking the
binding site of the target… irreversible damage.
DNA
Protein
1. An introduction to Medicinal Chemistry by Graham L. Patrick. 4th
edition, Oxford, 2009
2. Wilson and Gisvolds text book of organic medicinal and
pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th
edition, Lippincott Williams and Wilkings 2011.
3. Foyes principle of medicinal chemistry by David H. Williams, Thomas
L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th
edition, 2013.
