Drug Discovery Process-DK

Drug Discovery and Drug Design
by
Dr. Dhurke Kashinath

Assistant Professor
Department of Chemistry
National Institute of Technology Warangal-506 004
E-mail: kashinath.dhurke@gmail.com
20 October 2013
Dr. Dhurke Kashinath, NIT Warangal
Prescribed Texts:
Foyes Principles of Medicinal Chemistry David Williams and Thomas Lemke
Organic Chemistry of Drug design & Drug action-Richard Silverman,
Practice of medicinal chemistry-Wermuth, C.
An introduction to Medicinal Chemistry-Graham L Patrick
Pharmaceutical chemistry: Therapeutic aspects of biomacromolecules-Bladon,
Christin
Wilson & Giswolds textbook of Organic Medicinal & Pharmaceutical Chemistry
John Block
Comprehensive Medicinal Chemistry: The rational design, mechanistic study &
therapeutic application of chemical compounds Vol I VI, Hansch
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Medicinal Chemistry Folklore/traditional usage (History)

Examples:
Plant Ma Hung (Ephedra sinica)
used as heart stimulant, diaphoretic agent (perspiration producer)
and to relief from cough
Active ingredient ephedirin (a drug that raises the blood pressure
and relieves bronchial spasm; i.e. asthma )
Papaver somniferum (opium poppy)
3rd centuary B.C. opium popy juice used as an analgesic
10th centuary A.D. opium pills used for coughing, mental disorders,
aches and pain
Active ingredient morphine (potent analgesic) and codeine (cough
suppressant)
Bark of Cinchona trees
Used for fever in 1600 BC is used for malaria and fever even today
Active ingredient - quinine
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Introduction: Medicinal chemistry

Medicinal chemistry is the science that deals with design and discovery of
the new therapeutic chemicals and their development into useful medicines to
treat diseases
Medicinal chemistry involves isolation of compounds from nature or
synthesis of new molecules, structural elucidation (spectroscopic methods) and
study of their interactions with receptors, enzymes and DNA
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Objectives of Drug design:

(a) To understand the effects of synthetic/biological compounds on the basis of
molecular interaction with biological system
(b) To understand the processes by which the drugs usually produce their
pharmacological effects
(c) To understand how the drugs specifically react with the protoplasm to produce
a particular pharmacological response
(d) How the drugs usually get modified or metabolized and eliminated
from the body
(e) Probable relationship between biological activity with chemical structure
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Choosing the disease:

Diseases which are prevalent in developed countries
Impact on the society/Geographical consideration
Better properties than existing drugs
Economic factors
Identification of the target

Understanding the interactions of biomacromolecules (enzymes and receptors)
involved in a particular disease state
Design of agonist or antagonist for a particular receptor
Target specificity: electivity between species and body (organs and tissues)
Design of Agonist or antagonist
Identification of bioassay:
Choice of bioassay (finding out EC50, IC50, LD50)/therapeutic index
In vitro and In vivo tests and Test validity
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Modern drug discovery process
Target
identification
Target
validation
Lead
identification
Lead
optimization
2-5 years
Preclinical
Drug
phase
discovery
6-9 years
Drug discovery is an expensive process involving high R & D cost (10-15

million USD) and requires extensive clinical testing
A typical development time is estimated to be 10-15 years.
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Modern drug discovery process
10,000 molecules
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Early drug discovery (Preclinical)
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Drug discovery process (Clinical studies)
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Drug discovery process
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Background
View of living organisms as
molecular circuit:
Molecular circuit =
biochemical processes,
that form and recycle
molecules in a coordinated
and balanced fashion
Intended modes of
operation = healthy state
Aberrant modes of
operation = disease state
Diagnosis:
Identify the molecular
basis of disease
Therapy:
Guide biochemical circuit
back to healthy state
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Genomics - Proteomics
Mapping Sequence to Protein Structure and Dynamics
Primary Sequence
MNGTEGPNFY VPFSNKTGVV RSPFEAPQYY LAEPWQFSML AAYMFLLIML GFPINFLTLY VTVQHKKLRT PLNYILLNLA
VADLFMVFGG FTTTLYTSLH GYFVFGPTGC NLEGFFATLG GEIALWSLVV LAIERYVVVC KPMSNFRFGE NHAIMGVAFT
WVMALACAAP PLVGWSRYIP EGMQCSCGID YYTPHEETNN ESFVIYMFVV HFIIPLIVIF FCYGQLVFTV KEAAAQQQES
ATTQKAEKEV TRMVIIMVIA FLICWLPYAG VAFYIFTHQG SDFGPIFMTI PAFFAKTSAV YNPVIYIMMN KQFRNCMVTT
LCCGKNPLGD DEASTTVSKT ETSQVAPA
Folding
3D Structure
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This image cannot currently be display ed.
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Genomics - Proteomics
Mapping Sequence to Protein Structure, Dynamics and Function
Primary Sequence
MNGTEGPNFY VPFSNKTGVV RSPFEAPQYY LAEPWQFSML AAYMFLLIML GFPINFLTLY VTVQHKKLRT PLNYILLNLA
VADLFMVFGG FTTTLYTSLH GYFVFGPTGC NLEGFFATLG GEIALWSLVV LAIERYVVVC KPMSNFRFGE NHAIMGVAFT
WVMALACAAP PLVGWSRYIP EGMQCSCGID YYTPHEETNN ESFVIYMFVV HFIIPLIVIF FCYGQLVFTV KEAAAQQQES
ATTQKAEKEV TRMVIIMVIA FLICWLPYAG VAFYIFTHQG SDFGPIFMTI PAFFAKTSAV YNPVIYIMMN KQFRNCMVTT
LCCGKNPLGD DEASTTVSKT ETSQVAPA
Folding
3D Structure
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How to design a drug in the absence of a structure?

This image cannot currently be display ed.
Drug Target:
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Active site: Study and design of the lignad
1pth
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General terminology used in drug discovery:

Hit
Lead compound
Lead modification
Pharmacophore
DMPK
PK/PD
In-vivo
In-vitro
ADME
IC50
EC50
LD50
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Efficacy
Agonist
Antagonist
Prodrug
High throughput screening
Random screening
Therapeutic index
Drug resistance
CYPs (Cytochrome P 450)
CADD
Structure based drug design
Fragment based drug design
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Hit:
A hit is known or confirmed compound whose biological activity is known
(which is used for the primary screening)
Lead compound:
A lead compound is a representative of a compound series with sufficient
potential activity (as measured in terms of potency, selectivity,
pharmacokinetics, physicochemical properties, no toxicity and novelty) to
progress to a full drug development program
Lead discovery:
Lead discovery is the process of identifying active new chemical entities
(NCEs), which by subsequent modification may be transformed into a
clinically useful drug
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Lead optimization:
The synthetic modification of a biologically active compound, to fulfill all
stereoelectronic, physicochemical, pharmacokinetic and toxicological properties
required for clinical use.
The new lead optimization pattern demands that companies move to parallel
processes that evaluate binding affinity, ADME, drug properties, etc. earlier in
the process in order to cut the time and costs lost in failed leads.
Pharmacophore:
Essential part of the lead molecule which is important to show bilogical
activity and has to be kept intact during lead modification
Prodrug:
A prodrug is drug which is given (taken) in an inactive form. Once administered,
the prodrug is metabolized by the body (biochemical reactions) into a
biologically
20 October 2013 active compound Dr. Dhurke Kashinath, NIT Warangal
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DMPK:
Drug metabolism and pharmacokinetics

PK/PD:
Pharmacokinetics and pharmacodynamics studies of the molecules with

biological system (i. e. enzymes, receptors and nucleosides and nucleotides)
In-vitro and In-vivo studies:
In vitro studies which are performed in the laboratory on a similar (artificial)

biological system
In vivo studies which are performed on biological system (animal models)
ADME:
Administration, Distribution, Metabolism and Excretion

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Agonist:
An agonist is a chemical that binds to some receptor of a cell and triggers a

response by that cell
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Types of Agonists:
An agonist is a chemical that binds to some receptor of a cell and

triggers a response by that cell
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Antagonist:
An antagonist blocks the action of the agonist and an inverse agonist causes an
action opposite to that of the agonist
A receptor antagonist is a type of receptor ligand or drug that does not induce
a biological response itself upon binding to a receptor, but blocks or reduces
agonist-mediated responses
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HTS:
High throughput screening
IC50 (Inhibitory concentration):
Measure of the effectiveness of a compound in inhibiting biological or biochemical
function (IC50 represents the concentration of a drug that is required for 50% inhibition
in vitro)EC50 (Effective concentration):
The term half maximal effective concentration (EC50) refers to the concentration of a
drug, antibody or toxicant which induces a response halfway between the baseline and
maximum after a specified exposure time (the concentration of a compound where 50%
of its maximal effect is observed)LD50 (Lethal concentration):
In toxicology, the median lethal dose, LD50 (lethal concentration, 50%) or LCt50 (lethal
concentration & time) of a toxin, radiation, or pathogen is the dose required to kill half
the members of a tested population after a specified test duration
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Drug Discovery Without a Lead: Serendipitous discovery

Penicillin
First antibiotics discovered as natural products from the mold Penicillium
1928: Alexander Fleming noticed a green mold (Penicillium notatum) growing in
a culture of Staphylococcus aureus (gram positive bacteria)
Penicillin G and V isolated; antibiotic activity discovered; new -lactams
discovered and made through modification to give antibiotics with improved
activity.
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Penicillin-G ( R = benzyl), is the most potent of all penicillin derivatives

effective only against gram-positive bacteria
Undergoes metabolism in the stomach by gastric acids and is poorly and
irregularly absorbed into the blood stream
R = Ph/
substituted Ph
many disease producing staphylococci are able to produce an enzyme

capable of inactivating penicillin-G.
Other semi-synthetic derivatives:

Phenethicillin (Penicillin-V, R=PhOCH2) : Powerful electron-attracting
groups attached to the amino acid side chain prevent acid attack.
Methicillin (R=2,6-di-OCH3-C6H3-): A bulky group attached to the amino
acid side chain provides steric hindrance which interferes with the
enzyme attachment which would deactivate the penicillin
Ampicillin or Carbenicillin (R=C6H4NH2-): Increased polar character
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imparts a greater
activity
against
Gram-negative bacteria.
Dr. Dhurke
Kashinath,
NIT Warangal
27
Penicillin-G: Effective only against

gram-positive bacteria. Undergoes
metabolism in the stomach by gastric
acids and is poorly and irregularly
absorbed into the blood stream many
disease producing staphylococci are
able to produce an enzyme capable of
inactivating penicillin-G
-OH group at 4-position

better absorbed, following oral
administration
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Increased polar character

imparts a greater activity
against Gram-negative
bacteria
Electron-attracting groups
attached to the amino acid side
chain prevent acid attack
A bulky group attached to the

amino acid side chain
provides steric hindrance
which interferes with the
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Drug Discovery Without a Lead: Librium (Chlordiazepoxide)

Benzodiazepine tranquilizer (discovered while searching for anxiety drugs)
1957: Dr Leo Sternbach (Roche; Switzerland based company)
Librium
Benzheptoxdiazine
Originally planned to synthesize
Benzodiazepine 4 -oxide
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Quinazoline 3-oxide
X=7-Cl, R1=CH2NHCH3,
R2=C6H5
Submitted for
pharmacological
evaluation and found to
be Librium
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Finding a lead compound

Screening of natural products (plant kingdom, microbial world, marine
world, animal sources, venoms and toxins)
Medical folklore or Existing drugs
Screening synthetic compounds (series of compounds/libraries)
Starting from natural ligand or modulator (natural ligands for receptors,
enzymes, enzyme products as lead compounds, natural modulators as
lead compounds)
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Drug Discovery lead identification
Drug Discovery without a lead
Approaches for lead identification
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Penicillin
Librium
Random Screening
Nonrandom Screening
Drug Metabolism Studies
Clinical Observations
Rational Approaches to Lead Discovery
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Lead Modification
Identification of the Active Part of the molecule: The Pharmacophore
Pharmacophore: The relevant groups on a molecule that interact with a receptor (or an
enzyme) and are responsible for the activity are collectively known as pharmacophore
(Other atoms not part of the pharmacophore are part of the auxophore)
The pharmacophore can be used as a tool to design new drug molecules that can
interact with the same receptor
High blood pressure
(hypertension)
Losartan
(reference compound)
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Lead Modification
Which part has to be modified to improve drug action ???
Some of the atoms are essential to maintain the integrity of the molecule & hold the
pharmacophoric groups in their appropriate positions
While some are interfering with the binding of the pharmacophore, they need to be
excised/modified from lead compound
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Benzomorphan based drugs: Morphine as reference compound

Removal of half
of cyclohexene ring
Excising
the
dihydrofuran
ring
Levorphanol (4X)
Benzomorphan (<X)
Cutting away
methylene group
Morphine (X)
(Not much change)
(Reference compound)
Removal of all
fused ring
Acyclic analog
Methadone (X)
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Dr. Dhurke Kashinath, NIT (X/2)

Warangal
Dextropropoxyphene
Mepiridine (<X)
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Lead Modification:
Branching, isomerization, replacement of the rings, bioisosterism
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Lead compounds from natural receptor agonists

Examples:
Steroidal hormone progesterone (weakly active) acted as the lead compound
for contraceptive (+)-norgestrel
Serotonin (neurotransmitter) was used as a lead for anti-inflammatory

drug indomethacin [non-steroidal anti-inflammatory drug (NSAID)]
Drug Metabolism Studies:

Drug metabolites are degradation products generated in vivo
Drug metabolites are screened to determine if the activity is due to drug
candidate or from a metabolite
Anti-inflammatory drug
sulindac is inactive, its
metabolite is active
Antibacterial drug
sulfanilamide is a
metabolite of prontosil
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Pharmacokinetics (ADME)
(Absorption, Distribution/Transportation, Metabolism and Excretion)
Absorption movement of drug from
site of administration to blood [Rate of
dissolution, Surface area, Blood flow,
Lipid solubility, pH partitioning
Distribution (systemic circulation and
body tissues of the body)
Metabolism (generation of active species
and metabolites through enzymatic
biochemical reactions in the body:
cytochrome P450, hepatic microsomal
enzyme system)
Excretion
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The History of Chemotherapy

1910: Paul Ehrlich and Sahachiro Hata developed Salvarsan
(Arsphenamine) against syphilis (Starting of chemotherapy)
1928: Fleming discovered penicillin
1932: Sulfa drugs (sulfanilamide) discovered against Gram+ bacteria
1940: Howard Florey and Ernst Chain performed first clinical trials of
penicillin
Penicillinium colony
Inhibited area
Normal bacteria
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Features of antimicrobial Drugs

Antimicrobial drugs: Synthetic material, interfere with the growth of microbes
within the host
Antibiotic: Biological origin/produced by a microbe, inhibits/kills other
microbes
e.g. Bacteriostatic, Bactericidal
Selective toxicity (species): Drug kills pathogens without damaging the host
Therapeutic index: ratio between toxic dose and therapeutic dose or ratio of
LD50 to ED50 (High therapeutic index)
LD50 (low) vs. MIC and/or MBC (high)
Four major sites:
Cell wall, Ribosomes, DNA,
Antimicrobial action Bacteriostatic (inhibits the growth) vs
Bactericidal (kills bacteria)
Activity Spectrum:
Broad Spectrum Antibiotics: Effective against many types (E.g. Tetracycline);
Narrow Spectrum Antibiotics: Effective against very few types (E.g. Penicillin)
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The Action of Antimicrobial Drugs
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The Action of Antimicrobial Drugs
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Mechanism of action: Gram +Ve bacteria
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Mechanism of action: Gram Ve bacteria
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Retention of Penicillin G (Dose response curve)
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Inhibition of Protein Synthesis by Antibiotics
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Cephalosporins
Structure and mode of action resembles penicillins
1. More stable to bacterial lactamases than penicilins
2. Broader spectrum used
against penicillin-resistant
strains
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Vancomycin
Glycopeptide from Streptomyces
Inhibition of cell wall synthesis
used for Penicillin resistant Gram +Ve bacteria
Used to kill Methionine Sulfoxide Reductase A gene
Vancomycin resistance: Vancomycin-Resistant
Enterococcus (VRE) and Vancomycin-resistant
Staphylococcus aureus (VRSA)
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Antibiotic Resistance
A variety of mutations can lead to antibiotic resistance including the

following
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
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Resistance to Antibiotics
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Antibiotic Resistance
Misuse of antibiotics:
Using outdated or damaged antibiotics
Using antibiotics for the common cold and other problems in
inappropriate condition
Failing complete the prescribed regimen
Using someone else's leftover prescription
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Antiviral Drugs: Acyclovir DNA polymerase inhibitor

Nucleoside analogs inhibit DNA synthesis
Acyclovir and newer derivatives: Selective
inhibition of herpes virus replication.
Acyclovir converts in to nucleotide analog
only in virus infected cells very little
harm to uninfected cells!
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Antiviral Drugs: Acyclovir DNA polymerase inhibitor

Herps simplex virus
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Mechanism of Action of Acyclovir
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Antiviral Drugs for Treating HIV/AIDS:

HAART: Highly active antiviral therapy
1.
2.
3.
4.
NRTIs and NNRTIs

Protease Inhibitors
Fusion Inhibitors
Integrase Inhibitors
HIV protease cleaves viral polypeptide into functional proteins

Protease inhibition HIV cannot mature and noninfectious viruses are
produced.
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Antifungal Drugs
Fungal infections classification:
Superficial infections: Ringworm (tinea) skin and mucous
membrane. Incidence rate is high.
Systemic infections: Candida albicans opportunist infections.
Fatality rate is high.
Antifungal agents classification:
Antibiotics: Amphotericin B;
Azole: Ketoconazole;
Allylamine: Terbinafine;
Pyrimidine: Flucytosine.
Polyenes, such as nystatin and amphotericin B, used for systemic fungal
infections involve inhibition of ergosterol synthesis fungicidal
Griseofulvin from Penicillium. Systemic/oral. Binds to tubulin used for the
Tineae
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Antifungal Drugs
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Antiprotozoan and Antihelminthic Drugs

Examples of Antiprotozoan:
Chloroquine: Malaria (Plasmodium falciparum)
Metronidazole (Flagyl): Vaginitis, skin, joints infections and respiratory tract
caused by anaerobic bacteria
Examples of Antihelminthic:
Niclosamide and praziquantel: Tapeworm
Mebendazole: broadspectrum antihelmintic
Ivermectin: nematodes, mites, lice . . .
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Anti inflammatory drugs: How NSAIDs Help Relieve Pain ?

Block the effects of special enzymes called Cox-1 and Cox-2 enzymes
These enzymes play a key role in making prostaglandins
By blocking the Cox enzymes, NSAIDs stop body from synthesizing many
prostaglandins
Thus, less swelling and less pain
NSAIDs available over-the-counter drugs:
Aspirin (Bufferin, Bayer, and Excedrin)
Ibuprofen (Advil, Motrin, Nuprin)
Ketoprofen (Actron, Orudis)
Naproxen (Aleve)
NSAIDs are available by prescription:
Daypro, Indocin, Lodine
Naprosyn
Relafen
Voltaren
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Main Diseases of the Cardiovascular System

Hypertension: Increased sympathetic activity and sodium overload increase
blood pressure (BP)
Congestive heart failure: CHF due to weakening of the contractile function

of the heart. Blood and fluid accumulate in the heart, lungs, abdomen etc.
Coronary artery disease: Chest pain due to coronary artery disease (CAD)
and myocardial ischemia. Exertional angina (pain) usually occurs during physical
exertion or stress
Myocardial infarction: Caused by complete blockage of one of the coronary

arteries. Heart cells deprived of blood/oxygen become ischemic, die, and form
an infarct
Cardiac arrhythmias:
Disturbances in the normal electrical activity of the heart. Can be detected
on a recording of the electrocardiogram (ECG)
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Drug Classes Used to Cardio Vascular diseases:
Diuretics
Sympatholytic drugs
Vasodilator drugs
Calcium antagonist drugs
Angiotensin-converting enzyme inhibitor and angiotensin receptor blocking
drugs
Nitrites and nitrates
Beta adrenergic blocking drugs
Calcium antagonists, also referred to as calcium channel blockers
Cardiac glycosides
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Carcinogenesis
DNA mutation: Inactivation of tumor
supressor genes, binding to a virus
protein or binding to a mutated
cellular protein
Activation of protooncogenes to
oncogenes: point mutation (single
nucleotide polymorphisms-SNPs),
gene amplification, chromosome
translocation, virus interaction
Hereditary
Acquired: radiation, viruses, chemicals,
drugs
Characteristics of tumour cells:

Uncontrolled proliferation
Dedifferentiation & loss of function
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Types of cancers
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Drug Discovery and Drug Design

Dr. Dhurke Kashinath

Dr. Dhurke Kashinath, NIT Warangal

Dr. Dhurke Kashinath, NIT Warangal

Medicinal Chemistry Folklore/traditional usage (History)

Dr. Dhurke Kashinath, NIT Warangal

Introduction: Medicinal chemistry

Dr. Dhurke Kashinath, NIT Warangal

Objectives of Drug design:

Dr. Dhurke Kashinath, NIT Warangal

Choosing the disease:

Identification of the target

Dr. Dhurke Kashinath, NIT Warangal

Modern drug discovery process

Drug discovery is an expensive process involving high R & D cost (10-15

Dr. Dhurke Kashinath, NIT Warangal

Modern drug discovery process

Dr. Dhurke Kashinath, NIT Warangal

Early drug discovery (Preclinical)

Dr. Dhurke Kashinath, NIT Warangal

Drug discovery process (Clinical studies)

Dr. Dhurke Kashinath, NIT Warangal