Professional Documents
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20 October 2013
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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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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Target
identification
Target
validation
Lead
identification
Lead
optimization
2-5 years
Preclinical
Drug
phase
discovery
6-9 years
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10,000 molecules
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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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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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Drug Target:
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1pth
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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:
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Agonist:
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Types of Agonists:
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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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imparts a greater
activity
against
Gram-negative bacteria.
Dr. Dhurke
Kashinath,
NIT Warangal
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Electron-attracting groups
attached to the amino acid side
chain prevent acid attack
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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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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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Levorphanol (4X)
Benzomorphan (<X)
Cutting away
methylene group
Morphine (X)
(Reference compound)
Removal of all
fused ring
Acyclic analog
Methadone (X)
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Mepiridine (<X)
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Lead Modification:
Branching, isomerization, replacement of the rings, bioisosterism
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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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Inhibited area
Normal bacteria
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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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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
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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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1.
2.
3.
4.
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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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Coronary artery disease: Chest pain due to coronary artery disease (CAD)
and myocardial ischemia. Exertional angina (pain) usually occurs during physical
exertion or stress
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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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
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Types of cancers
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