1) The document discusses several different types of drug targets including enzymes like monoamine oxidase, cyclooxygenase, HMG-CoA reductase, dihydrofolate reductase, kinases, hydrolases, phosphodiesterases, carbonic anhydrase, and histidine decarboxylase. 2) It provides examples of drugs that target these enzymes, such as monoamine oxidase inhibitors, COX-2 inhibitors like celecoxib, statins, methotrexate, kinase inhibitors gefitinib, ACE inhibitors like captopril, PDE5 inhibitors like sildenafil, and carbonic anhydrase inhibitors acetazolamide. 3

1. Dr. Kumbhare Manoj R.
Professor, Head Dept. of Pharmaceutical Chemistry
S.M.B.T. College of Pharmacy, Dhamangaon
Tal- Igatpuri Dist. Nashik (M.S.).
mrkumbhare@rediffmail.com
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Drug target- Enzyme Inhibition

2. A: Enzymes
Enzymes are macromolecular biological catalyst
s. Enzymes accelerate, or catalyze, chemical
reactions. The molecules at the beginning of the
process upon which enzymes may act are
called substrates and the enzyme converts these
into different molecules, called products
2

3. Oxidoreductase enzymes play an
important role in both aerobic and
anaerobic metabolism. They can
be found in glycolysis, TCA cycle,
oxidative phosphorylation, and in
amino acid metabolism.
3

4. Monoamine oxidase inhibitors
A drug may be classified by the chemical type of the active
ingredient or by the way it is used to treat a particular
condition. Each drug can be classified into one or more
drug classes. monoamine oxidase inhibitors (MAO
inhibitors) inhibit one or both forms of the enzyme
monoamine oxidase and prevent the breakdown of
monoamine oxidase neurotransmitters. The substrate for
MAO-A enzyme is serotonin, melatonin, epinephrine and
norepinephrine and for MAO-B is phenylethylene.
Dopamine is a substrate for both the isoforms A and B.
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5. The MAOIs include isocarboxazid, phenelzine,
tranylcypromine, and selegiline, which was
developed for treatment of Parkinson’s disease rather
than depression.
Phenelzine is a non-selective and irreversible
monoamine (MAOI) of the hydrazine class which is
used as an antidepressant and anxiolytic.
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6. COX-1 and COX-2 inhibitors
By inhibiting prostaglandin synthesis, non-steroidal anti-
inflammatory drugs (NSAIDs) cause mucosal damage, ulceration
and ulcer complication throughout the gastrointestinal tract. The
recognition that there are two cyclo-oxygenase enzymes, one
predominating at sites of inflammation (COX-2) and one
constitutively expressed in the gastrointestinal tract (COX-1), has
led to the important therapeutic development of COX-2 inhibitors.
COX-2 is phylogenetically more primitive that COX-1 and, while
very similar, has critical differences, particularly the existence of a
small pocket half way down the active enzyme site. A number of
drugs achieve selectivity by binding to this pocket, including
presumptively rofecoxib and celecoxib.
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7. Celecoxib is a COX-2
selective nonsteroidal anti-
inflammatory drug (NSAID). It is used
to treat the pain and inflammation of
osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, acute
pain in adults, painful menstruation,
and juvenile rheumatoid arthritis in
people two years or older
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8. HMG-CoA reductase
8
(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase,
officially abbreviated HMGCR) is the rate-
controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-
dependent, EC 1.1.1.34) of the mevalonate pathway. Normally
in mammalian cells this enzyme is suppressed by cholesterol
derived from the internalization and degradation of low
density lipoprotein (LDL) via the LDL receptor as well as
oxidized species of cholesterol. Competitive inhibitors of the
reductase induce the expression of LDL receptors in the
liver, which in turn increases the catabolism of plasma LDL
and lowers the plasma concentration of cholesterol, an
important determinant of atherosclerosis.

9. This enzyme is thus the target of the widely available
cholesterol-lowering drugs known collectively as
the statins. Drugs that inhibit HMG-CoA reductase, known
collectively as HMG-CoA reductase inhibitors (or
"statins"), are used to lower serum cholesterol as a means
of reducing the risk for cardiovascular disease. These
drugs rosuvastatin ,lovastatin ,atorvastatin, pravastatin ,
fluvastatin , pitavastatin , and simvastatin.
Atorvastatin
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10. Dihydrofolate reductase, or DHFR, is
an enzyme that reduces dihydrofolic
acid to tetrahydrofolic acid,
using NADPH as electron donor, which can be
converted to the kinds of
tetrahydrofolate cofactors used in 1-carbon transfer
chemistry. Dihydrofolate reductase (DHFR) plays
an essential role in the formation of DNA by
managing folate, an organic molecule that shuttles
carbons to enzymes that need them for their
reactions.
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11. 11
Pyrimethamine
is a drug used to
treat parasitic infections,
namely toxoplasmosis andmalaria
(both as treatment and
prevention). Pyrimethamine is often
given with sulfadiazine, a
sulfonamide antibiotic, when treating
and providing secondary prevention
for people with HIV/AIDS

12. DHFR (Bacterial)
Dihydrofolate reductase, or DHFR, is an enzyme that
reduces dihydrofolic acid to tetrahydrofolic acid,
using NADPH as electron donor, which can be converted to the
kinds of tetrahydrofolate cofactors used in 1-carbon transfer
chemistry.
12
Trimethoprim is an inhibitor of
DHFR of micro-organisms, but
resistance to its action develops
quickly when it is used alone, so it
is usually combined with another
antibiotic

13. A transferase is any one of a class of enzymes that
enact the transfer of specific functional groups (e.g.
a methyl or glycosylgroup) from one molecule (called
the donor) to another (called the acceptor).
Transferases are also utilized during translation.
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14. Kinases are a class of enzymes that play a key role in
intracellular responses to stress and growth factors.
Kinases catalyse the transfer of phosphate from
adenosine triphosphate (ATP) to proteins, which may
be either other kinases, transcription factors or other
regulatory proteins. As such, activation of kinases leads
to a cascade of activating signals that regulate many
physiological processes, such as cell division and
differentiation. Aberrant kinase activity is associated
with many diseases like cancer, diabetes, and chronic
inflammatory disorders.
Kinases have been identified by the pharmaceutical
industry as important targets for drug development.
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15. 15
Tyrosine Kinase (Leishmanial, Bacterial and Human)
A tyrosine kinase is an enzyme that can transfer
a phosphate group from ATP to a protein in a cell. It functions
as an "on" or "off" switch in many cellular functions.
Tyrosine kinases are a subclass of protein kinase.
The phosphate group is attached to the amino acid tyrosine on
the protein. Tyrosine kinases are a subgroup of the larger class
ofprotein kinases that attach phosphate groups to other amino
acids (serine and threonine). Phosphorylation of proteins by
kinases is an important mechanism in communicating signals
within a cell (signal transduction) and regulating cellular
activity, such as cell division.
Protein kinases as drug targets in trypanosome and Leishmania

16. 16
Gefitinib is a drug used for
certain breast, lung and
other cancers. Gefitinib is
an EGFR inhibitor, like erlotinib,
which interrupts signaling
through the epidermal growth
factor receptor (EGFR) in target
cells. Therefore, it is only
effective in cancers with mutated
and overactive EGFR.

17. 17
Hydrolases (Mettaloproteases)
Hydrolases are hydrolytic enzymes, biochemical catalysts
that use water to cleave chemical bonds, usually dividing a
large molecule into two smaller molecules. Examples of
common hydrolases include esterases, proteases,
glycosidases, nucleosidases, and lipasesMettaloproteases-
A metalloproteinase, or metalloprotease, is
any protease enzyme whose catalytic mechanism involves
a metal. An example of this would be meltrin which plays a
significant role in the fusion of muscle cells during embryo
development, in a process known as myogenesis.
Most metalloproteases require zinc, but some use cobalt.
The metal ion is coordinated to the protein via
three ligands.

18. Angiotensin-converting enzyme (EC 3.4.15.1), or ACE, is a
central component of the renin-angiotensin system (RAS), which
controls blood pressure by regulating the volume of fluids in the
body. It converts the hormone angiotensin I to the active
vasoconstrictor angiotensin II. Therefore, ACE indirectly increases
blood pressure by causing blood vessels to constrict. ACE
inhibitors are widely used as pharmaceutical drugs for treatment
of cardiovascular diseases.
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Captopril
1) Hypertension 2) Cardiac conditions
such as congestive heart failure and
after myocardial infarction
3) Preservation of kidney function
in diabetic nephropathy

19. 1919
A carboxypeptidase (EC number 3.4.16 - 3.4.18) is
a protease enzyme that hydrolyzes (cleaves) a peptide bond at
the carboxy-terminal (C-terminal) end of a protein or peptide.
(Contrast with an aminopeptidase, which cleaves peptide bonds at
the other end of the protein.) Humans, animals, and plants contain
several types of carboxypeptidases that have diverse functions
ranging from catabolism to protein maturation.
CPE is involved in the biosynthesis of
most neuropeptides and peptide hormones

20. An esterase is a hydrolase enzyme that splits esters into an acid
and an alcohol in a chemical reaction with water called
hydrolysis. A wide range of differentesterases exist that differ in
their substrate specificity, their protein structure, and their
biological function.
In enzymology, an acetylesterase (EC 3.1.1.6) is
an enzyme that catalyzes the chemical reaction
Acetic ester + H2O an alcohol + acetate
An acetylcholinesterase inhibitor (often abbreviated AChEI)
or anti-cholinesterase is a chemical or a drug that inhibits
theacetylcholinesterase enzyme from breaking
down acetylcholine, thereby increasing both the level and
duration of action of theneurotransmitter acetylcholine.
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21. 21
Physostigmine is
a parasympathomimetic alkaloid,
specifically, a reversible cholinesterase
inhibitor. It occurs naturally in the
Calabar bean.

22. A phosphodiesterase (PDE) is an enzyme that breaks
a phosphodiester bond. Usually, phosphodiesterase refers
to cyclic nucleotidephosphodiesterases, which have great
clinical significance.
The cyclic nucleotide phosphodiesterases comprise a group
of enzymes that degrade the phosphodiester bond in
the second messengermolecules cAMP and cGMP.
A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is
a drug used to block the degradative action of cGMP-
specific phosphodiesterase type 5 (PDE5) on cyclic GMP in
the smooth muscle cells lining the blood vessels supplying
the corpus cavernosum of the penis.
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23. 23
Sildenafil, sold as Viagra and
other trade names, is a drug used
to treat erectile
dysfunction and pulmonary
arterial hypertension.
Its effectiveness for treating
sexual dysfunction in women has
not been demonstrated.

24. 24
Lyases
In biochemistry, a lyase is an enzyme that catalyzes the breaking
(an "elimination" reaction) of various chemical bonds by means other
than hydrolysis (a "substitution" reaction) and oxidation, often forming a
new double bond or a new ring structure. The reverse reaction is also
possible (called a "Michael addition”). For example, an enzyme that
catalyzed this reaction would be a lyase:
ATP → cAMP + Ppi
As a drug, it is used in the clinical treatment of Parkinson's
disease and dopamine-responsive dystonia. L-DOPA crosses the
protective blood–brain barrier, whereas dopamine itself cannot. Thus, L-
DOPA is used to increase dopamine concentrations in the treatment
of Parkinson's disease and dopamine-responsive dystonia.

25. Carbonic Anhydrase Inhibitors
acetazolamide and methazolamide are carbonic anhydrase inhibitors
used as diuretics and in the therapy of glaucoma. Both acetazolamide
and methazolamide have been linked to rare cases of clinically
apparent drug induced liver disease.
Acetazolamide, is a carbonic anhydrase inhibitor that is used for the
medical treatment of glaucoma, epileptic seizure, idiopathic
intracranial hypertension, altitude sickness, cystinuria, periodic
paralysis,central sleep apnea, and dural ectasia. Acetazolamide is
a diuretic.
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26. Histidine decarboxylase (HDC) is the enzyme that catalyzes
the reaction that produces histamine from histidine with the
help of vitamin B6 as follows:
Conversion of histidine to histamine by histidine decarboxylase
Dimenhydrinate is a combination of two
drugs: diphenhydramine and
8-chlorotheophylline
Dimenhydrinate antiemetic used for the
treatment of the symptoms of motion
sickness.
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