Introduction to Medicinal Chemistry(2).pptx

Unit I: Introduction to Medicinal Chemistry 8 hours
History of medicinal chemistry, Drugs of natural origin, Synthetic and
semisynthetic drugs, Drug discovery, Theoretic aspects of drug
design, Rational drug design.
Medicinal Chemistry I (Natural Drugs)
B. Pharm., Third Year, Fifth Semester
Ref:- 1. William O. Foye, Thomas L. Lemke and David A Williams: Principles of
Medicinal Chemistry, 2012, Lippincott Williams
2. An Introduction to Medicinal Chemistry - Graham Patrick

Medicinal chemistry includes synthetic & computational aspects of the study of
existing drugs and agents in development in relation to their bioactivities i.e.,
understandings a SARs (Structure Activity Relationships).
OR
It is a tailoring of drugs.

History of Medicinal Chemistry: -
 3500 BC : Sumerians report use of opium.
 3000 BC : Chinese report use of ma huang (ephedra)
 Greek Culture :
Hippocrates – followed teachings of Aristotle; focus is on the soul.
Galen – followed the teachings of Plato; focus is on experiment –
believed the whole could be explained by parts.

Paracelsus (1493–1541) glorified antimony and its salts in elixirs
as cure-alls in the belief that chemicals could cure disease.
The isolation of morphine by Friedrich Sertürner in 1803, the
isolation of emetine from ipecacuanha by Pierre-Joseph Pelletier in
1816, and his purification of caffeine, quinine, and colchicine in 1820 all
contributed to the increased use of “pure” substances as therapeutic agents.
1818 : Meissner proposes the general term alkaloids
The synthesis of acetic acid by Adolph Kolbe in 1845 and of methane by Pierre
Berthelot in 1856 set the stage for organic chemistry.

Albert Niemann isolated cocaine in 1860, and in 1864, he isolated the active
ingredient, physostigmine, from the Calabar bean.
1875 – Carl Buss isolates salicylic acid from Spirea ulmaria and shows that it is
an effective antipyretic – however, it is unpalatable and causes gastric distress.
1883 – von Nencki makes a salicylate ester with phenol, salol – it has very poor
solubility but is better tolerated. It is hydrolyzed slowly in the small intestine to
give to give salicylic acid – the first sustained release drug.
In the 19th century, digitalis was used by the English physician and botanist,
William Withering, for the treatment of edema.

Discovery of penicillin by Alexander Fleming in 1929 and its subsequent
examination by Howard Florey and Ernst Chain in 1941, led to a water-soluble
powder of much higher antibacterial potency and lower toxicity than that of
previously known synthetic chemotherapeutic agents.
Interest in synthetic chemicals that could inhibit the rapid reproduction of
pathogenic bacteria and enable the host organism to cope with invasive bacteria
was dramatically increased when the red dyestuff 2,4-diaminoazobenzene-4′-
sulfonamide (Prontosil) reported by Gerhard Domagk dramatically cured
dangerous systemic gram-positive bacterial infections in man and animals. (In
20th Century)

First used clinically by von Mering in 1893, paracetamol did not appear
commercially until 1950 in the United States and 1956 in Australia.
The 1920s and 1930s saw the recognition of vitamin deficiency diseases and the
elucidation of the structure of various vitamins.
Synthetic anti-malarials such as pamaquine (1926), mepacrine (1932) and later
chloroquine (1943) and paludrine (1946) were introduced as quinine
replacements.
The logical development during the 1960s of histamine antagonists for the
treatment of peptic ulcers led to cimetidine (1976) and then ranitidine (1981).

Drugs of natural origin
Drugs from natural origin have afforded poisons for darts and
arrows used in hunting and euphoriants with psychoactive properties
used in rituals.
The actual documentation of drugs derived from natural products in
the Western world appears to date as far back to the Sumerians and
Akkadians in the third century bce, as well as the Egyptian Ebers
Papyrus (about 1600 BCE).

In turn, the laboratory study of natural product drugs commenced
approximately 200 years ago, with the purification of morphine from
opium.
Additional drugs isolated from plant sources included atropine,
caffeine, cocaine, nicotine, quinine, and strychnine in the 19th
century, and then digoxin, reserpine, paclitaxel, vincristine, and
chemical precursors of the steroid hormones in the 20th century.

By the mid-20th century, therapeutically useful alkaloids had been
purified and derivatized from the ergot fungus, as uterotonic and
sympatholytic agents.
Then, the penicillins were isolated along with further major structural
classes of effective and potent antibacterials from terrestrial microbes.
Terrestrial microorganisms have been found to afford the largest
number of compounds currently used as drugs for a wide range of
human diseases, and these include antifungal agents, the “statin”
cholesterol-lowering agents, immunosuppressive agents, and several
anticancer agents.

Clinically useful drugs which have recently been isolated from plants
include the anticancer agent paclitaxel (Taxol) from the yew tree, the
antimalarial agent artemisinin from a Chinese plant, and the
Alzheimer’s drug galantamine from daffodils.
Antitumour agents derived from marine sources include eleutherobin,
bryostatins, dolastatins, cephalostatins, and halichondrin B.
Animals can sometimes be a source of new lead compounds. For
example, a series of antibiotic polypeptides known as the magainins
were extracted from the skin of the African clawed frog Xenopus
laevis.

Drugs of natural origin (advantages)
Potent and selective leads are obtained from various organisms.
A natural lead compound may help elucidate a new mechanism of
interaction with a biologic target for a disease state under investigation.
Natural products may serve to provide molecular inspiration in certain
therapeutic areas for which there are only a limited number of synthetic
lead compounds.
Secondary metabolites of organisms afford a source of small organic
molecules of outstanding chemical diversity.

Drugs of natural origin (disadvantages)
Resupply of the source organism of a secondary metabolite of interest
may prove problematic (isolated drug quantity may be in few mg only)
Natural product extracts have been regarded as incompatible with the
modern rapid screening techniques.
Generation of structural analogues to explore structure–activity
relationships and to optimize NP leads can be challenging.
Difficult to grow the plant/organism out of the natural habitat.

Synthetic and semisynthetic drug
Therapeutic agents are considered as natural, synthetic, or semi-synthetic
dependent on the source from which they were generated.
When the nucleus of the drug from natural source as well as its chemical
structure is altered, we call it synthetic drug.
E.g. Antipyretics, sulphonamides, antihistamines, anticonvulsants, anti
anxiety etc.
When the nucleus of drug obtained from natural source is retained but the
chemical structure is altered, we call it semi-synthetic drug.
Complex molecules Expensive and for impure natural compound E.g. 6-
aminopencillanic acid (fungus), semi-synthetic human insulin (pork
insulin).

Synthetic drug (advantages)
Synthesis can be faster than extraction (if reaction is of few steps).
Synthesis can be of lower cost than culture/cultivation, extraction,
processing and isolation.
Synthetic route if once valid and noted; very easily replicable.
Synthetic routes can provide compounds of higher purity and high
yield.
SAR of synthetic drugs can be established if similar compounds are
also synthesized.

Synthetic drug (disadvantages)
Synthesis can be slower than extraction (if reaction is of many steps).
Synthetic drugs can be costly; if starting material is costly and many
steps in reaction and purification are involved.
Synthetic route can be harmful for the environment e.g.heavy metals
Synthetic routes/contamination/degradation can accumulate some
highly toxic chemical as a by product(e.g., NMDA).
The drug metabolites produced from synthetic drug sources exert
fewer therapeutic effects with adverse side effects.

Need for Drug Discovery
 Unmet Medical Needs: New Diseases, AIDS, Alzheimer’s, Obesity
 Low efficacy – dementia, cancer
 Side effects – antipsychotics, antidepressants
 Downstream health cost - (Alzheimer’s; spinal injury)
 Cost of therapy; (Interleukins)
 Sustain industrial activity; pharmaceutical industry employs thousands and
makes a massive contribution to overseas earnings; patent expiry
Objective of Drug Discovery: - is to establish the most promising lead
compounds, which may be used as a therapeutic agent and facilitated with
treating medical conditions, including infections, cancer, nervous system
diseases, high blood pressure and metabolic diseases.

Drug development
The entire process of taking a newly discovered compound or drug through
regulatory approval to the point of marketing.
 During the development, the new drug or the compound should adhere to
high standards in the conduct, analysis and interpretation of preclinical and
clinical studies for its smooth passage through the regulatory approval
phase and eventually to marketing.
 Pathways of drug development are
a) Discovery
b) Preclinical development
c) Clinical development

Natural Products and drug discovery: -
 Historically, natural products have played a key role in drug discovery, especially for
cancer and infectious diseases, but also in other therapeutic areas, including
cardiovascular diseases (for example, statins) and multiple sclerosis (for example,
fingolimod).
 Nevertheless, natural products also present challenges for drug discovery, such as
technical barriers to screening, isolation, characterization and optimization, which
contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s
onwards.
 Recent technological and scientific advances that may help to overcome challenges in NP-
based drug discovery, with an emphasis on three areas: analytical techniques, genome
mining and engineering, and cultivation systems.

Advantages of Natural Products in drug discovery: -
 The higher rigidity of NPs can be valuable in drug discovery tackling protein–protein
interactions.
 Indeed, NPs are a major source of oral drugs.
 NPs are structurally ‘optimized’ by evolution to serve particular biological functions,
including the regulation of endogenous defence mechanisms.
 Their use in traditional medicine may provide insights regarding efficacy and safety.
 NP pool is enriched with ‘bioactive’ compounds covering a wider area of chemical space
compared with typical synthetic small-molecule libraries.

Disadvantages of Natural Products in drug discovery: -
 NP screens typically involve a library of extracts from natural sources, which may not be
compatible with traditional target-based assays.
 Accessing sufficient biological material to isolate and characterize a bioactive NP may also
be challenging.
 Gaining intellectual property (IP) rights for (unmodified) NPs exhibiting relevant
bioactivities can be a hurdle.
 Generation of structural analogues to explore structure–activity relationships and to
optimize NP leads can be challenging.
 Difficult to grow the plant/organism out of the natural habitat.

Outline of traditional bioactivity-guided isolation steps in natural
product drug discovery

 The process begins with extraction of NPs from organisms such as bacteria or
plants.
 The choice of extraction method determines which compound classes will
be present in the extract.
 Finally, at the last stage, when bioactive compounds are identified by
phenotypic assays, significant time and effort are typically needed to identify
the affected molecular targets.

Strategies to obtain natural product analogues with superior properties

 Unmodified natural products often possess suboptimal properties, and
superior analogues need to be obtained in order to yield valuable new
drugs.
 Tetracyclines are an example of NP-derived antibiotics that have already
yielded several generations of successfully marketed semisynthetic and
synthetic derivatives.
 The biosynthetic engineering approach has also shown potential; for
example, in the generation of analogues of rapamycin, bleomycin and
nystatin.

Lead in Drug Discovery: -
Lead (prototype bioactive molecule)
A lead compound, i.e. a "leading" compound, in drug discovery is a chemical
compound that has pharmacological or biological activity likely to be
therapeutically useful, but may nevertheless have suboptimal structure that
requires modification to fit better to the target.
Its chemical structure serves as a starting point for chemical modifications in
order to improve potency, selectivity, or pharmacokinetic parameters.

Finding a Lead in Drug Discovery: -
1. Screening of natural products
2. Medical folklore
3. Screening synthetic compound “libraries”
4. Starting from the natural ligand or modulator
5. Existing drugs
6. Combinatorial and parallel Synthesis
7. Computer-aided design of lead Compounds
8. Serendipity and the prepared mind

1. Screening of natural products
Plants have always been a rich source of lead compounds (e.g. morphine,
cocaine, digitalis, quinine, tubocurarine, nicotine , and muscarine ).
Microorganisms lead the discovery of penicillin, cephalosporins, tetracyclines ,
aminoglycosides , rifamycins , chloramphenicol, and vancomycin.
2. Medical folklore
The ancient records of Chinese medicine also provided the clue to the novel
antimalarial drug artemisinin. The therapeutic properties of the opium poppy
(active principle morphine ) were known in Ancient Egypt, as were those of the
Solanaceae plants in ancient Greece (active principles atropine and hyoscine)

3. Screening synthetic compound “libraries”
The thousands of compounds which have been synthesized by the
pharmaceutical companies over the years are another source of lead compounds.
It can also be worth testing synthetic intermediates. For example, a series of
thiosemicarbazones was synthesized and tested as antitubercular agents in the
1950s. This included isonicotinaldehyde thiosemicarbazone , the synthesis of
which involved the hydrazide structure isoniazid as a synthetic intermediate. It
was found subsequently that isoniazid had greater activity than the target
structure.

4. Starting from the natural ligand or modulator
The natural ligand of a target receptor has sometimes been used as the lead
compound. The natural ligands adrenaline and noradrenaline were the starting
points for the development of adrenergic β-agonists, such as salbutamol ,
dobutamine , and xamoterol, and 5-hydroxytryptamine (5-HT) was the starting
point for the development of the 5-HT1 agonist sumatriptan.
The natural substrate for HIV protease was used as the lead compound for
the development of the first protease inhibitor used to treat HIV.

5. Existing drugs
The aim is to modify the structure of existing sufficiently such that it
avoids patent restrictions, retains activity, and, ideally, has improved therapeutic
properties. For example, the antihypertensive drug captopril was used as a lead
compound by various companies to produce their own antihypertensive agents.
Most sulphonamides have been used as antibacterial agents. However, some
sulphonamides with antibacterial activity could not be used clinically
because they had convulsive side eff ects brought on by hypoglycaemia.
Structural alterations were made to the sulphonamides concerned in order to
eliminate the antibacterial activity and to enhance antibacterial activity.

Drug design:
 Drug design involves optimizing the binding interactions of a drug with its
target and to study pharmacokinetics.
 We must study both pharmacokinetic and pharmacodynamics of drug
because the compound with the best binding interactions for a target is not
necessarily the best drug to use in medicine.
 This is because a drug has to reach its target in the first place if it is to be
effective.
 Drug design helps the drug to get easily synthesized and make chemically
stable.
 It should be non-toxic and have acceptable pharmacokinetic properties.

Drug design: Traditional approach
 Traditional drug discovery involves the origin of drug discovery that evolved
in natural sources, accidental events etc.
 It was not target based and not much systemized as today.
 Improvement and advancement in pharmaceutical science and technology
made it revolutionized to much more systemized modern drug discovery.

Drug design: Traditional approach (Methods of Traditional Drug Design)
1. Random Screening
2. EthnoPharmacology Approach
3. Serendipity Method
4. Classical Pharmacology

1. Random Screening
It includes random screening of synthetic compounds/chemicals/natural products
by bioassay procedures.
It involves two approaches:-
a) Screening of selected class of compounds like alkaloids, flavonoids etc.
b) Screening of randomly selected plants.

2. EthnoPharmacology Approach
 Ethnopharmacology is the study of medicinal plants used in specific cultural
groups.
 It involves the observation, description, and experimental investigation of
indigenous drugs.
 It is based on botany, chemistry, biochemistry, pharmacology and many other
disciplines like anthropology, archeology, and history.
 Andrographis paniculata (Kalmegh) was used for dysentery in ethnomedicine
and the compounds responsible for the activity were found to be
andrographolides.

3. Serendipity Method
“Serendipity” refers to ‘an accidental discovery’ i.e, ‘finding one thing while
looking for something else’.
The most important example of this method is the discovery of Penicillin by
Alexander Fleming in 1928 while doing research on influenza.

4. Classical Pharmacology
 Also known as Function based approach.
 Without the prior identification of drug target.
 Anciently, drug discovery processes were often based on measuring a
complex response in-vivo such as
i) Prevention of experimentally induced seizures
ii) Lowering of blood sugar
iii) Suppression of inflammatory response

Drug design: Rational Drug Design (Deterministic approach)
 Rational drug design refers to the development of medications based on
the study of the structures and functions of target molecules.
Rational drug design can be broadly divided into two categories :-
A. Development of molecules with desired properties for targets having known
structure and function
B. Development of molecules with predefined properties for targets whose
structural information may be or may not be known.

Drug design: Rational Drug Design (Deterministic approach)
Methods for Rational drug design
Two major types :-
1) Structure Based Drug Designing
a) Docking
b) De novo drug design
2) Ligand Based Drug Designing
a) QSAR
b) Pharmacophore Perception

Structure based drug design (direct drug design)
 Relies on knowledge of the three dimensional structure of biological target
obtained through methods such as X- 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 affinity and selectivity to the target may be designed
using interactive graphics and the intuition of a medicinal chemist

 Structure based design is one of the first techniques to be used in the drug
design.
 Structure based drug design that has helped in discovery process of new
drugs .
 In parallel , information about the structural dynamics and electronic
properties about ligands are obtained from calculations .
 This has encouraged the rapid development of the structure based drug
design

Steps involved in structure based drug design
1. In structure guided drug design, a known 3D structure of a target bound to its
natural ligand or a drug is determined either by X-ray crystallography or by
NMR to identify its binding site.
2. Once the ligand bound 3D structure is known, a virtual screening of large
collections of chemical compounds.
3. Screening enables the identification of potential new drugs by performing
docking experiment of this collection of molecules. To enhance binding and
hence to improve binding affinity/specificity, a group of molecules with similar
docking scores is generally used for potency determination; this is High-
Throughput Screening (HTS).

Steps involved in structure based drug design
4. After the determination of biological potency, several properties such as
relationships (QSAR, QSPR, between potency and docking scores) including
statistical analysis can be performed to as- certain the potential molecule(s) for
lead drug discovery.

Docking: -
Docking refers to the ability to position a ligand in the active or a designed site
of a protein and calculate the specific binding affinities.
Docking algorithms can be used to find ligands and binding confirmation at a
receptor site close to experimentally determined structures.
Docking algorithms are also used to identify multiple proteins to which a small
molecule can bind.
Some of the docking programs are GOLD(Genetic optimization for ligand
Docking), AUTODOCK,LUDI,HEX etc.

Docking: -
Docking attempts to find the “best” matching between two molecules it includes
finding the Right key for the lock.
Given two biological molecules determine: Whether two molecules “interact” If
so, what is the orientation that maximizes “interaction” while minimizing the
total “energy” of the complex.
GOAL: To be able to search a database of molecular structures and retrieve all
molecules that can interact with the query structure.

Docking: -
Docking works by generating a molecular surface of proteins
Cavities in the receptor are used to define spheres (blue), the centres are potential
locations for ligand atoms.
Sphere centres are matched to ligand atoms , to determine possible orientations
for the ligand.

De Novo Drug Design
 De novo is a Latin expression meaning "from the beginning". Active site of
drug targets when characterized from a structural point of view will shed light
on its binding features.
 This information of active site composition and the orientation of various
amino acids at the binding site can be used to design ligands specific to that
particular target.
 The computer aided ligand design methods and distinguished them as six
major classes:
 Fragment location methods: To determine desirable locations of atoms or
small fragments within the active site.

2) Ligand Based Drug Designing (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 which
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, a quantitative structure-activity relationship (QSAR) in which
a correlation between calculated properties of 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.

Quantitative structure–activity relationship (QSAR)
 Quantitative structure–activity relationship is a widely used technique in
drug designing process.
 It employs statistics and analytical tools to investigate the relationship
between the structures of ligands and their corresponding effects.
 Hence, mathematical models are built based on structural parameters to
describe this structure–activity relationship.

2D-QSAR
 2D-QSAR was widely used to link structural property descriptors (such as
hydrophobicity, steric, electrostatic and geometric effects) to molecular
biological activity.
 The results were often analyzed with multiple regression analysis. One of
the most commonly used 2DQSAR methods was proposed by Hansch.
 2D-QSAR cannot accurately describe the correlation between the 3D spatial
arrangement of the physiochemical properties, and the biological activities,
so 3D-QSAR approaches have been adapted.

3D-QSAR
Frequently applied 3D-QSAR methodologies:
Comparative molecular field analysis (CoMFA)
The steric and electrostatic fields were calculated by CoMFA .
Comparative molecular similarity indices analysis (CoMSIA).
The CoMSIA method includes more additional field properties they are steric,
electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor.

Pharmacophore based approaches
 A pharmacophore is the ensemble of steric and electronic features that is
necessary to ensure the optimal supramolecular interactions with a specific
biological target and to trigger (or block) its biological response.
 The pharmacophore should be considered as the largest common denominator
of the molecular interaction features shared by a set of active molecules.
 Thus a pharmacophore does not represent a real molecule or a set of chemical
groups, but is an abstract concept.
 “A pharmacophore is the pattern of features of a molecule that is responsible
for a biological effect”.

Theoretic aspects of drug design, Rational drug design.
Drug Receptor Interactions
Influence of Physicochemical Properties of Drugs
on Biological Activity (Hydrophobicity, Electronic Influence, Steric Influence,)
Influence of Interactions of Drug with Non-target
Sites in Biological System (Some important biological parameters are protein
binding, tissue binding, interactions with
membrane lipids,including drug induced lipid
peroxidation, etc.)

Quantitative Structure-Activity Relationship (QSAR) Studies
Free Wilson Model

Introduction to Medicinal Chemistry(2).pptx

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