Introduction to Medicinal chemistry
Intended
Learning Objectives
At the end of this lecture, the student will be able to:
• Explain various aspects of Medicinal chemistry
Contents
• Introduction to medicinal chemistry
• Various Aspects of medicinal chemistry
Medicinal
chemistry
• Medicinal chemistry is a discipline at the intersection of
chemistry and pharmacology that involves the identification, synthesis, and
development of new chemical entities that are suitable for medical or
pharmaceutical use.
• It is an interdisciplinary science combining variety of
subjects such as organic chemistry, phytochemistry, pharmacology, toxicology,
molecular biology, biochemistry, computational chemistry, physical chemistry,
and statistics.
• It also includes the study of existing drugs, their
pharmacological properties, toxic effects, and their quantitative
structure-activity relationships (QSARs).
• Majority of the medicinal compounds, which are used as
medicines are natural products and synthetic organic compounds.
• However, metal-containing compounds are also found to be
useful as drugs.
– For example, cisplatin series of platinium-containing
complexes are used as anticancer agents. These are as metal-based drugs.
Medicinal
chemistry Objective
• The primary objective of medicinal chemistry is the design
and discovery of new compounds that are suitable for use as drugs.
• Medicinal chemistry defined by IUPAC
“It concerns the
discovery, the development, the identification and the interpretation of the
mode of action of biologically active compounds at the molecular level”
• The discovery or design of a new drug not only requires a
discovery process but also
the synthesis of the
drug, a method of administration,
the development of tests and procedures to establish how it operates in the
body and a safety assessment.
• Drug discovery may also require fundamental research into
the biological and chemical nature of the diseased state.
• These and other aspects of drug design and discovery
require input from specialists in many other fields and so medicinal chemists
need to have an outline knowledge of the relevant aspects of these fields.
Drug
• Drugs are strictly defined as chemical substances that are
used to prevent or cure diseases in humans, animals and plants.
• A very broad definition of a drug would include “all
chemicals other than food that affect living processes.”
• If the affect helps the body, the drug is a medicine.
• However, if a drug causes a harmful effect on the body,
the drug is a poison.
• The same chemical can be a medicine and a poison depending
on conditions of use and the person using it.
Pharmaceutical
effect
• The activity of a drug is its pharmaceutical effect on the
subject, for example, analgesic or b-blocker
• Its potency is the quantitative nature of that effect.
• Unfortunately the term drug is also used by the general
public to describe the substances taken for their psychotic rather than
medicinal effect
– However, these substances can also be used as drugs. E.g.
Heroin, is a very effective painkiller used in terminal cancer cases.
Side
effects
• Drugs act by interfering with biological processes, so no
drug is completely safe.
• All drugs, including non-prescription drugs, act as
poisons if taken in excess.
– E.g. overdoses of paracetamol can causes coma and death.
• All drugs have the potential for producing more than one
response.
• In addition to their beneficial effects most drugs have
non- beneficial biological effects.
– Aspirin, used to alleviate headaches, can also cause
gastric irritation and occult bleeding in some people.
• The non-beneficial effects of some drugs, .eg. cocaine and
heroin, are so undesirable that the use of these drugs has to be strictly
controlled by legislation.
• Unwanted effects appearing at therapeutic doses are called
side effects.
• However, side effects are not always non-beneficial;
– E.g. antihistamine- promethazine is licensed for the
treatment of hay fever but also induces drowsiness, which may aid sleep.
• In contrast, adverse drug effects appearing at extreme
drug doses are described as toxic effects.
Greeks used–pharmakon–
for both poisons and medicinal products.
Drug
resistance – Tachyphylaxis
• Drug resistance or tolerance occurs when a drug is no longer
effective in controlling a medical condition.
– Acute, sudden decrease in response to a drug after its
administration, i.e. a rapid and short-term onset of drug tolerance.
– It can occur after an initial dose or after a series of
small doses
• It arises in people
for a variety of reasons.
– For example, the effectiveness of barbiturates often
decreases with repeated use because the body develops mixed function oxidases
in the liver that metabolize the drug, which reduces its effectiveness.
– The development of an enzyme that metabolizes the drug is
a relatively common reason for drug resistance.
– Another general reason for drug resistance is the down
regulation of receptors
– Downregulation occurs when repeated stimulation of a
receptor results in the receptor being broken down. This results in the drug
being less effective because there are fewer receptors available for it to act
on.
• Drug resistance may also be due to the appearance of a significantly
high proportion of drug-resistant strains of microorganisms.
Drug
discovery – Stages
Medicinal chemistry covers the following stages:
(i) The first stage new active substances
or drugs are identified and prepared from natural sources, organic chemical
reactions or biotechnological processes.
• They are known as lead molecules.
(ii) The second stage
is optimization of lead structure to improve potency, selectivity and to reduce
toxicity.
(iii) Third stage
is development stage, which involves optimization of synthetic route for bulk
production and modification of pharmacokinetic and pharmaceutical properties of
active substance to render it clinically useful.
Need for
Novel drugs
• New drugs are constantly required to combat drug resistance
even though it can be minimized by the correct use of medicines by patients.
• They are also required for improving the treatment of
existing diseases
• The treatment of newly identified diseases
• The production of safer drugs by the reduction or removal of
adverse side effects.
Receptor
• A large number of drugs act through specific macromolecular
components of the cell, which regulate critical functions like enzymatic
activity, permeability, structural features, template function etc.
• These macromolecules, which bind and interact with the
drugs, are called receptors.
• A receptor is
a component of
a cell or
organism that interacts with a
drug and initiates the chain of biochemical events leading to the drug’s
observed effects.
Theory of
receptors
• Theory of receptors has become one of the fundamental concepts
of medicinal chemistry.
• Receptor sites -usually take the form of pockets, grooves
or other cavities in the surface of certain proteins and glycoproteins in the
living organism.
– They should not be confused with active sites- regions of
enzymes where metabolic chemical reactions occur.
• Binding of a chemical agent – ligand- to a receptor sets
in motion a series of biochemical events that result in a biological or
physiological effect.
– Side effects arise when the drug binds to the receptor
responsible for the desired biological response or to different receptors.
Pharmacophore
• The section of the structure of a ligand that binds to a receptor
is known as its pharmacophore
• A part of a molecular structure that is responsible for a
particular biological or pharmacological interaction that it undergoes
• IUPAC definition of a pharmacophore is: A pharmacophore is
the ensemble of steric and electronic features that is necessary to ensure the
optimal supramolecular interactions with a specific biological target structure
and to trigger (or to block) its biological response
Agonist
Agonist—A drug that
activates a receptor
is knows as agonist, which has following properties;
– Agonists can differ in both affinity and efficacy for the
receptor
– High efficacy agonists are full agonists because they
elicit maximal effects
– Low efficacy agonists are partial agonists because they
cannot elicit a maximal effect at receptors even at high concentrations
– Direct agonists act on receptors, while indirect agonists
facilitate the actions of the endogenous agonist (the neurotransmitter, itself)
Antagonist
• Antagonist—A drug that does not activate the receptor is antagonist,
which possess the following features;
– Antagonists also prevent the activation of the receptor by
an agonist, thus antagonists are essentially zero efficacy drugs
– Competitive antagonists bind to the same binding site as
the agonist and therefore compete with the agonist for that binding site
– Non-competitive antagonists have a different binding site
to the agonist and therefore do not compete with the agonist.
Receptor
site theory
• After attachment of drug molecule to a receptor site, a drug
may either initiate a response or prevent a response from occurring.
– consider ‘lock-and-key’ principle for ligand–receptor
interaction.
– Only keys (ligands) that fulfill all criteria for fitting
into the lock (receptor) can open the door (produce an effect).
– Some keys can fit in the lock but not perfectly,
consequently they cannot open the door, but they prevent the original key from
fitting into the lock and opening the door.
– The concept of receptor antagonism is very often the
underlying mechanism of drug action
– e.g. to prevent the constriction of airways in asthmatic
conditions, receptor antagonists
are administered-they prevent
the actions of
the signaling molecules causing
muscle contraction (e.g. histamine antagonists)
One could regard an antagonist
as an imperfect key and a receptor agonist as the perfect key.
Structure–activity
relationship (SAR)
• Structure–activity relationship (SAR) is a method which consists
of synthesizing and testing a series of structurally related compounds.
• It hence give the relation between the structure of the
compound and its activity
• Quantitative measurements incorporated into structure– activity
relationship determinations- QSAR
– e.g Successful use of QSAR -development of the antiulcer
agents cimetidine and ranitidine in the 1970s
• Both SAR and QSAR are important parts of the foundations
of medicinal chemistry.
Names of
Drugs
• International Nonproprietary Names (INN)
Use of INN
• Nonproprietary names are intended for use in
pharmacopoeias, labelling, product information, advertising and other
promotional material, drug regulation and scientific literature, and as a basis
for product names, e.g. for generics.
• National names – British Approved Names (BAN), Dénominations
Communes Françaises (DCF), Japanese Adopted Names (JAN) and United States
Adopted Names (USAN) are, with rare exceptions, identical to the INN.
Pharmacokinetic
Parameters
Pharmacokinetics is the study of:
• Absorption
• Distribution
• Metabolism
• Elimination
Absorption
• Amount of drug that reaches the systemic circulation (bioavailability)
is highly dependent on absorption
• Properties of the drug, route of administration and
patient factors should be considered to ensure clinical effectiveness
• Most drugs are absorbed into the systemic circulation via passive
diffusion
• Other mechanisms of absorption include: active transport,
facilitated diffusion, pinocytosis/phagocytosis
• Absorption rate and amount depends on local blood flow at
administration site (eg. sublingual vessels provide significant blood flow
therefore rapid absorption)
Factors
Affecting Absorption
• Molecular size:
– Small size, water
soluble drugs can
pass through channels
in membranes, large molecules cannot
• Local pH and drug
ionization:
– Charged molecules do not cross membranes
• Total surface area
for absorption:
– Small intestine has villi which increase the surface area
for absorption, and hence is the primary site of absorption for most oral drugs
Distribution
• Process by which drugs are carried throughout the body to reach
target sites of action
• Volume of Distribution (Vd)
• Actual volume of distribution (Vd): Anatomic volume that
is accessible to drug, e.g. total body water – 40 L
Protein
Binding
• Drug molecules in the blood are in two forms:
• Bound to plasma proteins – example, albumin, globulin
• Free form (unbound)
Principles of Protein
Binding
• Free drug can distribute into tissues and exert its
action, and is subject to metabolism and elimination
• Affinity of a protein binding site for a drug determines
bound/unbound concentrations, and reversibility of interaction
• Saturation of binding sites may result in a large increase
in unbound drug concentration, which could cause toxicity
• Decrease in albumin concentration (liver failure or nephrotic
syndrome), can lead to toxicity of highly bound drug
• Competition for binding sites between drugs and endogenous
substrates can result in interactions and toxicity
• Significant drug interactions can occur due to competitive
protein binding
Metabolism
• Main site of biotransformation in the body is the ‘LIVER’
• Drug metabolizing enzyme pathways generally mediate 2
types of reactions:
• Phase I reactions (includes, oxidation, reduction and hydrolysis)
• Phase II reactions (includes, conjugation)
Elimination
• Different routes of elimination include:
• Stool (e.g. corticosteroids from biliary system)
• Kidneys (main site of drug elimination)
• Lungs (e.g. general anesthetics eliminated by expiration)
• Skin and mucous membranes (e.g. rifampin in tears)
“Kidneys” the Main
Organ of Elimination
• Glomerular filtration
• Passive, pore size about 400-600 Angstroms
• Tubular secretion
• Active, against concentration gradient, saturable,
• Tubular reabsorption
• Can be active or passive (depending on charge)
Summary
• Medicinal chemistry is a discipline at the intersection of
chemistry and pharmacology that involves the identification, synthesis, and
development of new chemical entities that are suitable for medical or
pharmaceutical use.
• Drugs are defined as chemical substances that are used to
prevent or cure diseases in humans, animals and plants.
• The activity of a drug is its pharmaceutical effect on the
subject
– For example, analgesic or antipyretic
• Its potency is the quantitative nature of that effect
• Unwanted effects appearing at therapeutic doses -side
effects.
• The macromolecules, which bind and interact with the drugs,
are called receptors
• The section of the structure of a ligand that binds to a receptor
is known as its pharmacophore
• Agonist—A drug that activates a receptor is knows as agonist
• Antagonist—A drug that does not activate/or prevents the
activation of the receptor is known as antagonist
• Structure–activity relationship (SAR) is a method which
consists of synthesizing and testing a series of structurally related
compounds.
– It hence give the relation between the structure of the
compound and its activity
• Pharmacokinetics is the study of: Absorption,
Distribution, Metabolism, and Elimination