INTRODUCTION

In medicinal chemistry, the chemist attempts to

design and synthesize a pharmaceutical agent that
has a desired biological effect on the human body
or some other living system. Such a compound
could also be called a ‘drug’, but this is a word that
many scientists dislike because society views the
term with suspicion. With media headlines such as
‘Drugs Menace’, or ‘Drug Addiction Sweeps City
Streets’, this is hardly surprising. However, it
suggests that a distinction can be drawn between
drugs that are used in medicine and drugs that are
abused. Is this really true?

“Drug is any chemical substance that affects the

functioning of living things and the organisms
(such as bacteria, fungi, and viruses) that infect
them.”

Until the mid-19th century the approach to drug

therapeutics was entirely empirical. This thinking

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changed when the mechanism of drug action
began to be analyzed in physiological terms and
when some of the first chemical analyses of
naturally occurring drugs were performed. The end
of the 19th century signaled the growth of
the pharmaceutical industry and the production of
the first synthetic drugs. Chemical synthesis has
become the most important source of therapeutic
drugs, although genetic engineering is developing
as a means of synthesizing proteins.

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DRUG DESIGNING

Drug design, sometimes referred to as rational

drug design or more simply rational design, is the
inventive process of finding new medications based
on the knowledge of a biological target. The drug is
most commonly an organic small molecule that
activates or inhibits the function of a biomolecule
such as a protein, which in turn results in a
therapeutic benefit to the patient. In the most
basic sense, drug design involves the design of
small molecules that are complementary in shape
and charge to the biomolecular target with which
they interact and therefore will bind to it. Drug
design frequently but not necessarily relies on
computer modeling techniques. This type of
modeling is often referred to as computer-aided
drug design. Finally, drug design that relies on the
knowledge of the three-dimensional structure of

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the biomolecular target is known as structure-
based drug design.

TYPES OF DRUG DESIGN

I. LIGAND-BASED DRUG DESIGN

Ligand-based drug design (or indirect drug design)

relies on knowledge of other molecules that bind to
the biological target of interest. These other
molecules may be used to derive a pharmacophore
model that defines the minimum necessary
structural characteristics a molecule must possess
in order to bind to the target In other words, a
model of the biological target may be built based
on the knowledge of what binds to it, and this
model in turn may be used to design new
molecular entities that interact with the target.
Alternatively, Quantitative Structure-Activity
Relationship (QSAR) is a method in which a
correlation between calculated properties of

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molecules and their experimentally determined
biological activity may be derived. These QSAR
relationships in turn may be used to predict the
activity of new analogs.

II. STRUCTURE-BASED DRUG DESIGN

Structure-based drug design (or direct drug design)

relies on knowledge of the three dimensional
structure of the biological target obtained through
methods such as x-ray crystallography or NMR
spectroscopy. If an experimental structure of a
target is not available, it may be possible to create
a homology model of the target based on the
experimental structure of a related protein. Using
the structure of the biological target, candidate
drugs that are predicted to bind with high affinity
and selectivity to the target may be designed using
interactive graphics and the intuition of a medicinal
chemist

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As experimental methods such as X-ray
crystallography and NMR develop, the amount of
information concerning 3D structures of
biomolecular targets has increased dramatically. In
parallel, information about the structural dynamics
and electronic properties about ligands has also
increased. This has encouraged the rapid
development of the structure-based drug design.

DRUG TARGET

The main molecular targets for drugs are proteins

(mainly enzymes, receptors and transport
proteins), and nucleic acids (DNA and RNA). These
are large molecules (macromolecules) having
molecular weights measured in the order of several
thousand atomic mass units. They are much bigger
than the typical drug, which has a molecular
weight in the order of a few hundred atomic mass
units. The interaction of a drug with a
macromolecular target involves a process known
as binding. There is usually a specific area of the

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macromolecule where this takes place, and this is
known as the binding site

Typically, this takes the form of a hollow or canyon

on the surface of the macromolecule allowing the
drug to sink into the body of the larger molecule.
Some drugs react with the binding site and become
permanently attached via a covalent bond that has
bond strength of 200–400 kJ mol1. However, most
drugs interact through weaker forms of interaction
known as intermolecular bonds.

TYPES OF INTERMOLECULAR BONDS

ELECTROSTATIC OR IONIC BONDS

An ionic or electrostatic bond is the strongest of

the intermolecular bonds (20–40 kJ mol) and takes
place between groups having opposite charges
such as a carboxylate ion and an alkylammonium
ion. The strength of the interaction is inversely
proportional to the distance between the two
charged atoms, and it is also dependent on the

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nature of the environment, being stronger in
hydrophobic environments than in polar
environments.

HYDROGEN BONDS

A hydrogen bond can vary substantially in strength

and normally takes place between an electron-rich
heteroatom, and electron-deficient hydrogen. The
electron-rich heteroatom has to have a lone pair of
electrons and is usually oxygen or nitrogen.

VAN DER WAALS INTERACTIONS

Van der Waals interactions also referred to as

London forces are very weak interactions, typically
2–4 kJ mol in strength, that involve interactions
between hydrophobic regions of different
molecules. These regions could be aliphatic
substituents or the carbon skeleton of the

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molecules concerned. Although the interactions are
individually weak, there may be many such
interactions between a drug and its target and so
the overall contribution of van der Waals
interactions can often be crucial to binding.
Hydrophobic forces are also important when the
non-polar regions of molecules interact

DIPOLE–DIPOLE AND ION–DIPOLE

INTERACTIONS

Many molecules have a permanent dipole moment

resulting from the different electronegativities of
the atoms and functional groups present. It is
possible for the dipole moments of the drug and
the binding site to interact as a drug approaches,
aligning the drug such that the dipole moments are
parallel and in opposite directions

DRUG METABOLISM

Drug metabolism is the biochemical modification of

pharmaceutical substances by living organisms,

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usually through specialized enzymatic systems.
This is a form of xenobiotic metabolism. Drug
metabolism often converts lipophilic chemical
compounds into more readily excreted polar
products. Its rate is an important determinant of
the duration and intensity of the pharmacological
action of drugs.

Drug metabolism can result in toxication or

detoxication - the activation or deactivation of the
chemical. While both occur, the major metabolites
of most drugs are detoxication products.

Drugs are almost all xenobiotics. Other commonly

used organic chemicals are also xenobiotics, and
are metabolized by the same enzymes as drugs.
This provides the opportunity for drug-drug and
drug-chemical interactions or reactions.

PHASES OF DRUG METABOLISM

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 PHASE I

Phase I reactions (also termed nonsynthetic

reactions) may occur by oxidation, reduction,
hydrolysis, cyclization, and decyclization, carried
out by mixed function oxidases, often in the liver.
These oxidative reactions typically involve a
cytochrome P450 monooxygenase, NADPH and
oxygen. The classes of pharmaceutical drugs that
utilize this method for their metabolism include
phenothiazines, paracetamol, and steroids.

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 PHASE II

Phase II reactions — usually known as conjugation

reactions are usually detoxicating in nature, and
involve the interactions of the polar functional
groups of phase I metabolites. Sites on drugs
where conjugation reactions occur include carboxyl
(-COOH), hydroxyl (-OH), amino (NH2), and
sulfhydryl (-SH) groups. Products of conjugation
reactions have increased molecular weight and are
usually inactive unlike Phase I reactions which
often produce active metabolites.

DRUG-ENZYME INTERACTION

Main role of drugs is to either increase or decrease

role of enzyme catalyzed reactions. Inhibition of
enzymes is a common role of drug action. Enzyme
inhibitor is drug which inhibits catalytic activity of
enzymes or blocks the binding site of the enzyme
and eventually prevents the binding of substrate
with enzyme. Drug can inhibit attachment of
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substrate on active site of enzymes in following
ways:

COMPETITIVE INHIBITION

Competitive Inhibitors are the drugs that compete

with the natural substrate for their attachment on
the active sites of enzymes.

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NON-COMPETITIVE INHIBITION

Some drugs do not bind to the enzyme’s active

site, instead bind to a different site of enzyme
called allosteric site. This binding of inhibitor at
allosteric site changes the shape of the active site
in such a way that substrate cannot recognize it. If
the bond formed between an enzyme and an
inhibitor is a strong covalent bond and cannot be
broken easily, then the enzyme is blocked
permanently. The body then degrades the enzyme-

inhibitor complex and synthesizes the new enzyme

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RECEPTORS AS DRUG TARGETS

Proteins which are vital for communication system

in the body are called receptors. In the body,
message between two neurons and that between
neurons to muscles is communicated through
chemical messengers. They are received at the
binding sites of receptor proteins. To accommodate
a messenger, shape of the receptor site changes
which brings about the transfer of message into
the cell. Chemical messenger gives message to the

cell without entering the cell.

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Receptors show selectivity for one chemical
messenger over the other because their binding
sites have different shape, structure and amino
acid composition.

Drugs that bind to the receptor site and inhibit its

natural function are called antagonists. These are
useful when blocking of message is required. Drugs
that mimic the natural messenger by switching on
the receptor are called agonists. These are useful
when there is lack of natural chemical messenger.

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TYPES OF DRUGS

ANTIPYRETICS

Chemical substances which are used to bring down

the temperature in high fevers are called
Antipyretics.

The most common antipyretics are paracetamol,

phenacetin, analgin and
aspirin.

PARACETAMOL ASPIRIN

ANALGESICS

Chemical substances used for relieving pain are

called Analgesics.

Classification of Analgesics:

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NON-NARCOTIC ANALGESICS NARCOTIC ANALGESICS

They are non-addictive drugs When administered in medicinal doses, these drugs relieve
pain and produce sleep

Examples: Aspirin, Ibuprofen, Naproxen, Dichlofenac Sodium Examples: Morphine, codeine.

IBUPROFEN MORPHINE

ANTISEPTICS

Antiseptics are chemical substances that kill or

prevent growth of microorganisms and can be
applied on living tissues such as cuts, wounds etc.

Dettol, a mixture of parachlorometaylenol and

terpineol, is a commonly used antiseptic for
wounds, cuts etc.

Soframycin is an antiseptic ointment.

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 PARACHLOROMETAYLENOL TERPINEOL

DISINFECTANTS

Disinfectants are chemical substances that kill

microorganisms but cannot be applied on living
tissues such as cuts, wounds etc.

Phenol (1%), iodoform, etc are

commonly used disinfectants.

PHENOL

TRANQUILIZERS/SEDATIVES

Tranquilizers are chemical substances used for the

treatment of stress and mild or severe mental
diseases. Tranquilizers are also called psycho-
therapeutic drugs.

Iproniazid and Phenelzine are Anti-depressant

drugs.

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 IPRONIAZID MEPROBAMATE

ANTIMICROBIALS

Drugs that tends to destroy/prevent development

or inhibit the pathogenic action of microbes such
as bacteria (antibacterial drugs), fungi (antifungal
agents), virus (antiviral agents), or other parasites
(antiparasitic drugs) selectively.

SULPHADIAZINE ARSPHENAMINE

ANTIBIOTICS

Chemical substances produced by microorganisms

that kill or prevent the growth of other microbes

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Classification of antibiotics on basis of mode of
control of microbial diseases:
BACTERICIDAL BACTERIOSTATIC

Drugs that kills organisms in body Drugs that inhibits growth of organisms

Examples: Examples:
Penicillin, Aminoglycosides, Erythromycin, Tetracycline,
Ofloxacin Chloramphenicol

Classification of antibiotics on basis of its spectrum

of action:
BROAD SPECTRUM ANTIBIOTICS NARROW SPECTRUM ANTIBIOTICS LIMITED SPECTRUM ANTIBIOTICS

Antibiotics which kill or inhibit a wide Antibiotics which are effective mainly Antibiotics effective against a single
range of Gram-positive and Gram- against Gram-positive or Gram- organism or disease
negative bacteria negative bacteria

Examples: Examples: Penicillin G

Vancomycin and Ofloxacin

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 PENICILLIN OFLOXACIN

ANTIFERTILITY DRUGS

Antifertility Drugs are chemical substances used to

prevent conception or fertilization. These drugs
control the female menstrual cycle and ovulation.

Norethindrone and Ethinylestradiol are commonly

used in birth control pills.

NORETHINDRONE ETHINYLESTRADIOL

ANTIHISTAMINES

Antihistamines are amines which are used as drugs

to control the allergy effects produced by
histamines. Histamine is found naturally in nearly
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all body tissues which are released in allergic
conditions.

Common antihistamine drugs are

Chlorpheniramine, Terfenadine, and Promethazine.

TERFENADINE

ANTACIDS
Antacid are chemical substances which neutralize
excess acid in the gastric juices and give relief
from acid indigestion, acidity, heart burns and
gastric ulcers.
Common antacids are Cemetidine and Ranitidine.

CEMETIDINE
RANITIDINE

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 CONCLUSION

Drugs produce harmful as well as beneficial effects,

and decisions about when and how to use them
therapeutically always involve the balancing of
benefits and risks. Drugs approved for human use
are divided into those available only with a
prescription and those that can be bought freely
over the counter. The availability of drugs for
medical use is regulated by law.

The law is different in each country. A drug can be

legal in one country and illegal in another. It
suggests that a distinction can be drawn between
drugs that are used in medicine and drugs that are
abused but it is impossible to do so.

‘Everything is a poison, nothing is a poison. It is the

dose that makes the poison’.

Almost anything taken in excess will be toxic. You

can make yourself seriously ill by taking 100

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aspirin tablets or a bottle of whisky or 9 kg of
spinach. The choice is yours!

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