A seminar on the pharmacodynamic effects of drugs on enzymes along with their applications. Presented on 07/08/2019 Handout: 1) Introduction & history of enzymes 2) Nomenclature & classification of Enzymes (NC-IUBMB) 3) Structure of enzymes - Shape, active & allosteric sites 4) Mechanism of action of enzymes- Substrate binding, catalysis, dynamics, allosteric modulation 5) Role of enzymes 6) Enzymes as drug targets 7) Enzyme inhibition by drugs: A) Targeted clinical effects by enzyme Inhibition B) Enzyme kinetics C) Types of enzyme inhibition - Competitive, Non competitive & uncompetitive inhibition D) Adverse drug reactions due to enzyme inhibition 8) Enzyme activation by drugs 9) Microsomal enzymes as drug targets 10)Transmembrane receptors linked to enzymes: A) Tyrosine Kinase pathway B) JAK-STAT pathway C) Serine Threonine Pathway D) Toll like Receptors E) TNF-α Receptors 11) Summary with system-wise drugs acting on enzymes 12) Newly Approved Drugs 13) Conclusion 14) References

1. Targets of Drug Action:
Enzymes
Dr. Rajmohan Seetharaman
1st yr Resident
Department of Pharmacology,
Lokmanya Tilak Muncipal
Medical College, Sion (w),
Mumbai, 400022.
1

2. Overview
2
• Introduction & history of enzymes
• Nomenclature & classification of Enzymes
• Structure & mechanism of action of enzymes
• Role of enzymes
• Enzymes as drug targets
• Enzyme inhibition by drugs
1. Their targeted clinical effects
2. Enzyme kinetics & types of inhibition
3. Adverse drug reactions due to enzyme inhibition

3. Overview
3
• Enzyme activation by drugs
• Microsomal enzymes as drug targets
• Transmembrane receptors linked to enzymes
• Summary with system-wise drugs acting on enzymes
• Newly Approved Drugs
• Conclusion
• References

4. Introduction
4
Enzymes: Biologic polymers -> catalyze chemical
reactions facilitating the conversion of substrates to
products -> very integral role in our existence.

5. History of Enzymes
5
• 17th and early 18th centuries -> Digestion
of meat & conversion of starch to sugars
were known
• In 1833 -> French chemist Anselme Payen
-> first to discover an enzyme, diastase.
• In 1877 -> German physiologist Wilhelm
Kühne (1837–1900) first used the term
enzyme -> comes from Greek word
"leavened" or "in yeast”

6. Nomenclature & classification of enzymes
6
• Enzymes are usually named according to the reaction they carry
out
• The suffix -ase is combined with the name of the substrate
e.g., lactase is the enzyme that cleaves lactose
• They are also named according to the type of reaction
e.g., DNA polymerase forms DNA polymers
The Nomenclature Committee of the International Union of
Biochemistry and Molecular Biology (NC-IUBMB) classifies
enzymes into families, on the basis of the reactions they catalyse.

7. Table:Classification of enzymes
7
EC Class Function Examples
EC 1 Oxidoreductases
Reduction-Oxidation
reactions
Monoamine Oxidase
EC 2 Transferases Move a chemical group Protein-tyrosine kinase
EC 3 Hydrolases
Hydrolysis; Bond cleavage with
transfer of functional group of
H2O
dipeptidyl-peptidase IV
EC 4 Lyases
Non Hydrolytic Bond
cleavage
ATP citrate lyase
EC 5 Isomerases Intramolecular group transfer Topoisomerase
EC 6 Ligases
Synthesis of new covalent bond
between substrates using ATP
hydrolysis
DNA ligase
There are six main families:
Murray R. Harper's illustrated biochemistry. 31st ed. New York: McGraw-Hill Medical; 2018.

8. Structure of Enzymes
8
• Globular proteins, acting alone or in larger
complexes.
• Consists of a binding site & a catalytic site.
• The catalytic site: the small portion of
their structure directly involved in
catalysis.
• Can act as receptors by binding with their
substrates at their binding site.
• Contains allosteric sites -> binding of a
small molecule causes a conformational
change -> increases or decreases activity.
The catalytic site and
binding site together
comprise the enzyme's
active site.
Action on allosteric site
E.g. Carbonic
Anhydrase inhibitor
Murray R. Harper's illustrated biochemistry. 31st ed. New York: McGraw-Hill Medical; 2018.

9. Mechanism of action of Enzymes
9
1) Substrate binding
• Enzymes must bind their substrates before they can catalyse any chemical
reaction & they are very specific as to what substrates they bind
Lock & Key Model
• Proposed by Emil Fischer in 1894
• The enzyme and the substrate possess
specific complementary geometric
shapes that fit exactly into one
another.
• There is no change in the active site
before & after a chemical reaction
Induced Fit Model
• In 1958, Daniel Koshland suggested a
modification to the lock and key model.
• The active site is reshaped by interactions
with the substrate which allows the
substrate to bind with the enzyme.

10. Mechanism of action of Enzymes (continued)
10
2) Catalysis
• Enhance reaction rates -> lowering the activation
energy of reactions & stabilising the reaction molecule
(at their activated complex sites).

11. Mechanism of action of Enzymes (continued)
11
3) Dynamics
• Enzymes are not rigid, static structures; instead they have
complex internal dynamic motions.
• Different dynamic motions of an enzyme may be associated
with different aspects of an enzyme's function.
4) Allosteric modulation
• The binding of molecules to allosteric site -> change in the
conformation or dynamics of the enzyme -> transduced to
the active site -> affects the reaction rate of the enzyme.
• Allosteric interactions can either inhibit or activate enzymes.
Murray R. Harper's illustrated biochemistry. 31st ed. New York: McGraw-Hill Medical; 2018.

12. Role of Enzymes
12
• Enzymes are used for in various industries when
extremely specific catalysts are required.
• Enzymes in the Food industry: E.g. Lactase, Protease,
etc.
• Enzymes in the Textile Industry: E.g. Cellulase
• Enzymes as diagnostics: E.g. Alkaline Phosphatase,
Creatine Kinase- MB
• Enzymes as Drug Targets: ACE inhibitors, PDE
inhibitors
• Enzymes in therapeutics: Serratiopeptidase, β-
lactamases, tPA

13. 13
Enzymes as drug targets
Targets of Drug Action
• Receptors
• Transporters
• Ion Channels
• Enzymes

14. 14
• Drugs inhibiting enzymes bind to the enzyme and
decreases its activity.
• It hence slows down or blocks enzyme catalysis.
• Most of the drugs currently used are enzyme inhibitors.
• 47% of all current drugs inhibit enzyme targets
Enzyme Inhibition by Drugs
Ramsay R, Tipton K. Assessment of enzyme inhibition: a review with examples from the development of monoamine oxidase
and cholinesterase inhibitory drugs. Molecules. 2017;22(7):1192.

15. Clinical effects targeted by inhibiting enzymes
15
Alter levels of
normal physiological
molecules
Correct chemical
deficiencies
Block enzyme
activity in
pathophysiology
Correct chemical
excess
Inhibit biochemical
pathways
Inhibitors

16. 16
1) To Alter levels of normal physiological cellular molecules in
pathologies

17. 17
Vigabatrin
Valproate
2) To correct chemical deficiencies by using enzyme inhibitors
for enzymes which use that chemical as its substrate

18. 18
3) To block enzyme activity of enzymes that play a role in
pathophysiology

19. 19
4) To correct chemical excess by inhibiting the enzyme that
produces the molecule itself

20. 20
5) To Inhibit biochemical pathways unique to a pathogen which can
reduce the growth or kill a pathogen - bacteria, virus or a parasite

21. 21
5) To Inhibit biochemical pathways unique to a pathogen which
can reduce the growth or kill a pathogen (continued)

22. Enzyme Kinetics
22
• Michaelis-Menten equation is the rate equation for an
enzyme catalyzed reaction
• The formula is:
][
][max
0
SK
SV
V
m +
=
Where,
V0 is the initial velocity
Vmax is the maximum velocity
[S] is the substrate concentration
Km (Michaelis-Menten constant) is the substrate concentration at which
the reaction velocity is the half of the maximum velocity.

23. Enzyme Kinetics
Lineweaver-Burk Plot ( Double Reciprocal Plot)
23
• It is a graph between 1/Substrate on X axis & 1/V on Y
axis.
• It is used to determine enzyme kinetics & type of
enzyme inhibition

24. Competitive Inhibition by drugs
24
• Any compound which resembles a chemical structure &
molecular geometry of substrate.
• The inhibitor binds only to the enzyme & not to the
enzyme-substrate complex.

25. 25
Competitive Inhibition kinetics

26. 26
Enzyme inhibitor depends on:
• Inhibitor concentration
• Substrate concentration
• Relative affinities of inhibitor & substrate for active site
Competitive Inhibition (Continued)

27. 27
E.g. Methanol Poisoning
Competitive Inhibition examples

28. 28
E.g. Methotrexate used in Cancers
Competitive Inhibition examples

29. 29
E.g. Carbidopa competes with levodopa for dopa
decarboxylase
Competitive Inhibition examples

30. 30
Competitive Inhibition examples
Diisopropyl-fluorophosphate (DIFP) organophosphates
irreversibly inhibit steric site of acetyl cholinesterase

31. 31
Competitive Inhibition examples
Enzyme Endogenous Substrate Competitive Inhibitor
Cholinesterase
Acetylcholine
Physostigmine,
Neostigmine
Monoamine-oxidase A
(MAO-A)
Catecholamines Moclobemide
Dihydropteroate Synthase
Para-amino benzoic acid
(PABA)
Sulfadiazine
Xanthine oxidase Hypoxanthine Allopurinol
Angiotensin converting
enzyme (ACE)
Angiotensin-1 Captopril
5α-Reductase Testosterone Finasteride
Aromatase
Testosterone,
Androstenedione
Letrozole, Anastrozole
Tripathi K. Essentials of medical pharmacology. 7th ed. New Delhi, India: Jaypee Brothers; 2013.

32. Non-Competitive inhibition by drugs
32
• Substance that reacts with the enzyme but at the
allosteric site.
• It binds to the Enzyme as well as the ES complex with
equal affinity.

33. 33
Non Competitive Inhibition kinetics

34. 34
Non Competitive Inhibition examples
E.g. Effect of Disulfiram on Aldehyde Dehydrogenase

35. 35
E.g. Echinocandins 1,3-β glucan synthase inhibitors
Non Competitive Inhibition examples
Wiederhold NP, Lewis RE. The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy. Expert opinion on
investigational drugs. 2003 Aug 1;12(8):1313-33.

36. 36
Non Competitive Inhibition examples
E.g. Antiplatelet effect of Aspirin on COX-1
Sharma S, Sharma SC (October 1997). "An update on eicosanoids and inhibitors of cyclooxygenase enzyme systems". Indian J. Exp. Biol. 35
(10): 1025–31. PMID 9475035

37. 37
Non Competitive Inhibition examples
E.g. Effect of Alloxanthine on Xanthine Oxidase

38. 38
Non Competitive Inhibition examples
Non Competitive Inhibitor Enzyme
Acetazolamide Carbonic anhydrase
Omeprazole H+ K+ ATPase
Digoxin Na+ K+ ATPase
Theophylline Phosphodiesterase
Propylthiouracil Peroxidase in thyroid
Lovastatin HMG-CoA reductase
Sildenafil
Phosphodiesterase-5
Tripathi K. Essentials of medical pharmacology. 7th ed. New Delhi, India: Jaypee Brothers; 2013.

39. Uncompetitive Inhibition by drugs
39
• These molecules can bind reversibly to the enzyme
when the substrate is already bound to the active site
• The inhibitor binds to the E-S Complex.
• This is a very rare type of inhibition.

40. 40
Vmax is decreased but the apparent Km will decrease as well
due to the selective binding of the inhibitor to the ES species
Uncompetitive Inhibition kinetics

41. Uncompetitive Inhibition examples
41
E.g. Lithium and the phosphoinositide cycle
Nahorski SR, Ragan CI, Challiss RJ. Lithium and the phosphoinositide cycle: an example of uncompetitive inhibition and its
pharmacological consequences. Trends in pharmacological sciences. 1991 Jan 1;12:297-303.

42. Suicide Inhibitor drugs
42
• Suicide inhibition, also known as suicide inactivation or
mechanism-based inhibition.
• Irreversible form of enzyme inhibition -> when an
enzyme binds an inhibitor
• It forms an irreversible complex with it during the
reaction.
• The complex reacts irreversibly to form a stable
inhibitor-enzyme complex.

43. Suicide Inhibitor drugs examples
43
• β-Lactamase inhibitors inhibit β-Lactamase enzyme to
prevent hydrolysis of Penicillins.

44. Suicide Inhibitor drugs
44
Name Mechanism of Action
Disulfiram Aldehyde Dehydrogenase inhibitor
Exemestane Aromatase inhibitor
Eflornithine Ornithine decarboxylase inhibitor
Acyclovir Viral DNA polymerase inhibitor
Erythromycin CYP3A4 inhibitor
Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.

45. Hit & Run Drugs
45
• Are drugs whose effects lasts longer than the drug itself
• A drug with a relatively short t1/2 is still able to produce
effect long after it has been eliminated
• Examples: MAO-inhibitors, Methyldopa, Omeprazole,
Guanethidine, Reserpine, Aspirin.

46. 46
Adverse Reactions due to Enzyme inhibition by drugs
Enzyme Inhibitor Substrate Adverse reaction
ACE Captopril, Lisinopril Bradykinin Cough, Angioedema
Acetyl cholinesterase Neostigmine Acetylcholine
Abdominal cramps,
nausea, vomitting
Cyclo-oxygenase Diclofenac Arachidonic acid
Peptic ulceration,
nephrotoxicity
ALDH Metronidazole Acetaldehyde
Disulfiram like
reaction
DHFR Methotrexate Dihydro Folic Acid Megaloblastic Anemia
MAO A Moclobemide Catecholamines Hypertensive crisis
Phosphodiesterase-5 Sildenafil Cyclic GMP (cGMP)
Blue Green tinted
vision

47. Enzyme activation by drugs
47
• Enzyme activity can be accelerated through biochemical
modification of the enzyme.
• It is theoretically possible to bind molecules to enzymes
to increase catalysis (enzyme activators).
• These molecules must bind to a site other than the
substrate binding site
• There are conditions where enzyme activators could be
of benefit therapeutically.

48. 48
• Heparin acts as an anticoagulant by activating
antithrombin III
Enzyme activator drugs examples

49. 49
• Pralidoxime, which reactivates cholinesterase in
poisoning with organophosphorus insecticides
Enzyme activator drugs examples

50. Enzyme activator drugs examples
50
Reactivation of AchE is no longer possible if:
• It has undergone Ageing
• Poisoning is due to Carbamate poisoning
• Poisoning due to overdose of physostigmine,
neostigmine
Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.

51. 51
• Phenobarbitone -> Prevention and
Treatment of Unconjugated
Hyperbilirubinemia in Preterm
Neonates -> glucuronyl transferase
Bilirubin to Glucuronic acid
• Cushings syndrome: Phenytoin
reduce the manifestations
degradation of adrenal steroids
which are produced in excess.
Chronic Poisonings -> Self inducers ->
induce their own metabolism
Microsomal Enzymes as drug targets
Tripathi K. Essentials of medical pharmacology. 7th ed. New Delhi, India: Jaypee Brothers; 2013.

52. 52
• Receptor Tyrosine Kinases.
• Jak-STAT Receptor.
• Receptor Serine-Threonine Kinases
• Toll-like Receptors
• TNF-α Receptors.
•
Transmembrane Receptors Linked to Intracellular Enzymes
Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.

53. 53

54. 54
(MAPKKK)
(MAPKK)
Receptor Tyrosine Kinases
EGFR receptor
phosphorylated
EGF
RAS (phosphorylated)
Gets attached to accessory
proteins Grb2, SOS
RAF (Phosphorylated)
MEK ( Phosphorylated)
MAPK (phosphorylated)
MNK, RSK, MYC
Transcription
Grb 2: Growth Factor receptor-bound protein 2
SOS: Son of Sevenless
RAF: Rapidly Accelerated Fibrosarcoma
MAPK: Mitogen-activated protein kinase

55. 55
EGF, PDGF, VEGF
EGFR,
PDGFR,
VEGFR
Cell survival,
proliferation &
differentiation
MNK,
RSK,
MYC
Tyrosine Kinase -
MAP Kinase
cross-
phosphorylation

56. 56
Drugs acting on Tyrosine Kinase Pathway
Mechanism Drug Indication
Monoclonal antibodyEGFR
kinase inhibitors
Cetuximab
Metastatic colorectal cancer
with wild type KRAS
Small molecule EGFR Kinase
Inhibitor
Erlotinib Advanced pancreatic cancer
Small molecule HER2 Kinase
inhibitors
Lapatinib HER2 positive breast cancer
Monoclonal Antibody HER2
Kinase inhibitors
Trastuzumab
HER2 positive breast cancer
with gastric cancer
Platelet derived growth
factor inhibitors
Olaratumab Soft tissue sarcoma
Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.

57. 57
Drugs acting on Tyrosine Kinase Pathway
Mechanism Drug Indication
Mutant B-RAF Kinase
Inhibitors
Vemurafenib
BRAFV600E/K Mutant
melanoma
MAP Kinase Inhibitors Cobimetinib
BRAF600E/K Mutant
melanoma
Cyclin dependent kinase 4/6
inhibitors
Palbociclib
Advanced ER positive, HER2
negative breast cancer
VEGF inhibitor Bevacizumab Metastatic colorectal cancer
Bruton Tyrosine Kinase
inhibitors
Ibrutinib Mantle cell lymphoma, CLL
Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.

58. 58
• Insulin
Drugs acting on Tyrosine Kinase Pathway
Insulin
Binds to Tyrosine kinase receptors
α subunits induces aggregation and
internalization
activates tyrosine kinase activity of the β
subunits
Phosphorylates tyrosine residues of IRS1
& IRS2
cascade of phosphorylation and
dephosphorylation reactions
stimulation or inhibition of enzymes
involved in the rapid metabolic actions
of insulin.

59. Jak-STAT Receptor Pathway
59
JAK-STAT: Jannus Kinase/ Signal transducer & activator of
transcription
There are four Jaks and six STATs in mammals that, depending
on the cell type and signal, combine differentially to activate
gene transcription
Cytokine binds with receptor
Receptor gets dimerized
Phosphorylates JAK
Phosphorylates STAT
2 phosphorylated
STAT`s combine
with each other
(Dimers)
STAT dimer goes into nucleus
Transcription

60. 60
Cytokine
Cytokine
Receptor
Immunological
processes such as
apoptosis &
inflammation
STAT
Dimer
JAK-STAT cross
phosphorylation

61. 61

62. 62
Types of JAK`s & STAT`s
JAK4

63. 63
Drugs acting on JAK-Stat Pathway
Name Indication Inhibiting Enzyme
Ruxolitinib
Polycythemia Vera,
myelofibrosis
JAK1/JAK2
Tofacitinib
psoriasis and rheumatoid
arthritis.
JAK3
Oclacitinib
pruritus associated with
allergic dermatitis
JAK1
Baricitinib rheumatoid arthritis JAK1/JAK2
Fedratinib
primary myelofibrosis or
secondary myelofibrosis
JAK2
Upadacitinib rheumatoid arthritis JAK1
Khanna P; et al. The JAK/STAT signaling cascade in gastric carcinoma (Review) [J]. International Journal of Oncology. 2015, 47(5):1617.

64. Receptor Serine-Threonine Kinases
64
Activin/TGFβ BMP
Smad 2/3 Smad 1/5
Smad 4
Transcription
Type II recruits type I &
phosphorylates it

65. 65
Activin/
TGFβ/
BMP
Activin/
TGFβ/
BMP
Receptor
regulation of cell
proliferation,
programmed cell
death
(apoptosis), cell
differentiation,
and embryonic
development.
Smad 4
Serine Threonine
kinase
phosphorylation

66. Toll-like Receptors
66
Lipids, Peptidoglycans, Viruses
Dimerisation of Receptor
Recruits adaptor protein MyD88
Recruits IRAK4, IRAK1 & IRAK2
Phosphorylate TRAF6
Polyubiquinates itself
Interacts with TAK1, TAB1 & TAB2
TAK1 phosphorylates IKK-β,
which then phosphorylates IκB
IκB degrades allowing NFκB to diffuse into
the cell nucleus and activate transcription
MyD88: Myeloid Differentiating Factor 88
TRAF6: TNF receptor associated factor 6
IRAK: Interkeukin receptor Activated Kinase
TAK: TNF receptor associated kinase
IKK-β inhibitor of nuclear factor kappa-B kinase subunit beta
nuclear factor kappa-light-chain-enhancer of activated B cells

67. 67
Lipids,
Peptidoglycans
, viruses
Toll like
receptors
Role in the
innate immune
system.
NFκB
MyD88-IRAK-
TAK- IKK-β
phosphorylation

68. Toll-like Receptors types
68

69. 69
Drugs acting on Toll-like Receptor pathway
Ligand Phase TLR Indication
Pembrolizumab Phase II TLR 3 Agonist
Metastatic colon
cancer
Romidepsin Phase I TLR 3 Agonist
Cutaneous T cell
lymphoma
Eritoran Phase II TLR 4 antagonist Insulin sensitivity
Imiquimod Phase II TLR 7 agonist HPV
Ibudilast Phase II TLR 4 antagonist Glioblastoma
Entolimod Phase I TLR5 Agonist
Unspecified adult
solid tumor
Hydroxychloroquine Phase III TLR 9 Inhibitor Sjogren's syndrome
Anwar MA, Shah M, Kim J, Choi S. Recent clinical trends in Toll-like receptor targeting therapeutics. Medicinal research reviews. 2019 May;
39(3):1053-90.

70. TNF-α Receptors
70
TNFα binds to TNFR
dissociation of the inhibitory protein SODD
TRADD binds to DD
Recruits
TRAF2
& RIP
Recruits
IKK
IκBα
degraded
NF-κB released &
causes transcription
Activation
of JNK
group
Translocation
into nucleus
TRADD
binds to
FADD
Recruits
Caspase 8
Cell Death
TRAF 2: TNF receptor-associated factor 2
RIP: Receptor Interacting Protein
SODD: Silencer of Death Domains
IKK-β inhibitor of nuclear factor kappa-B kinase subunit beta
nuclear factor kappa-light-chain-enhancer of activated B cells

71. 71
TNFα
TNFR
1) Inflammation
2) Cell differentiation
& proliferation
3) Apoptosis
1)NF-κB
2) STAT
3) Caspase 8
1) TRAF2-RIP - IKK
pathway
2) JNK Pathway
3) TRADD- FADD
pathway

72. 72
Drugs acting on TNF-α Receptor pathway
Name FDA Approved Indication
Etanercept Nov.1998 Rheumatoid arthritis, Psoriatic arthritis,
Ankylosing spondylitis, Plaque psoriasis
Infliximab Aug. 1998
Rheumatoid arthritis, Psoriatic arthritis,
Ankylosing spondylitis, Plaque psoriasis
Crohn’s disease, Pediatric RA & Pediatric
Crohn’s
Adalimumab
Dec. 2002
Rheumatoid arthritis, Psoriatic arthritis, Plaque
psoriasis, Active ankylosing spondylitis, Crohn’s
disease, Juvenile idiopathic arthritis
Golimumab Apr. 2009. Rheumatoid arthritis, Psoriatic arthritis, Plaque
psoriasis, Ulcerative Colitis
Certolizumab Pegol Apr. 2008 Rheumatoid arthritis, Psoriatic arthritis,
Ankylosing spondylitis, Crohn’s disease
Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants–past, present and
future. Cytokine & growth factor reviews. 2014 Aug 1;25(4):453-72.

73. 73
Summary: System-wise Drugs acting on Enzymes
Autonomic Nervous System
Class Drugs Mechanism
Anticholinesterases
Physostigmine, Rivastigmine,
Tacrine, Dyflos, Malathione,
Carbaryl, Propoxur
Acetyl cholinesterase inhibitors
Acetyl cholinesterase
reactivators
Pralidoxime, Obidoxime,
Diacetyl mono-oxime
Acetyl cholinesterase
reactivators

74. 74
Summary:System-wise Drugs acting on Enzymes
Autocoids
Class Drugs Mechanism
NSAIDS
Aspirin, Ibuprofen,
Nimesulide, Paracetamol
COX inhibitor
Anti Gout Allopurinol, Febuxostat Xanthine Oxidase inhibitor
Antimetabolites Methotrexate Dihydro Folate Reductase inhibitor
Immunomodulators Leflunomide
Dihydro-orotate dehydrogenase
inhibitor
Immunomodulators Mycophenolate Mofetil
Cytosine monophosphate
dehydrogenase inhibitor

75. 75
Summary: System-wise Drugs acting on Enzymes
Nephrology
Class Drugs Mechanism
Diuretics
Acetazolamide, Dorzolamide,
methazolamide
Carbonic Anhydrase inhibitors
Indirect ET Receptor
antagonists
Phosphoramidon, CGS 35066
Endothelin Converting Enzyme
inhibitors
Antihypertensives Captopril, Enalapril, Lisinopril
Angiotensin Converting
Enzyme Inhibitors

76. 76
Summary: System-wise Drugs acting on Enzymes
Cardiovascular System
Class Drugs Mechanism
Bipyridines Mirlinone, Cilostazole Phosphodiesterase-3-inhibitor
Antiplatelet Dipyridamole
Adenosine deaminase inhibitor
Phosphodiesterase inhibitor
Cardiac Glycosides Digoxin, Digitoxin Na+/K+ ATPase inhibitor
Statins
Atorvastatin, Simvastatin,
Lovastatin
HMG COA Reductase Inhibitor
Fibrates
Gemfibrozil, Bezafibrate,
Fenofibrate
Lipoprotien Lipase Activators

77. 77
Summary: System-wise Drugs acting on Enzymes
Endocrinology
Class Drugs Mechanism
Antiestrogens Letrozole, Anastrazole Aromatase inhibitor
Antiandrogens Finasteride, Dutasteride 5-α-Reductase Inhibitor
Erectile dysfunction drugs Sildenafil, Tadalafil Phosphodiesterase-5-inhibitor
Antithyroid PTU, Carbimazole Thyroid Peroxidase inhibitor
Antidiabetics Insulin Tyrosine Kinase activator
Antidiabetics Sitagliptin, Saxagliptin Dipeptidyl Peptidase-4 inhibitor
Antidiabetics Acarbose, Miglitol, Voglibose α-Glucosidase inhibitor
Antidiabetics Biguanides Metformin AMP-activated protein kinase
activator

78. 78
Summary: System-wise Drugs acting on Enzymes
GIT
Class Drugs Mechanism
Proton Pump Inhibitors
Omeprazole, Pantoprazole,
Lansoprazole, Dexlansoprazole,
Rabeprazole, Esomeprazole
H+/K+ ATPase inhibitor

79. 79
Summary: System-wise Drugs acting on Enzymes
CNS
Class Drugs Mechanism
Antimaniac Lithium IMPase inhibitors
Antidepressants MAO AI Moclobemide, Clorgyline MAO A inhibitors
Antiparkinsonian MAO BI Selegiline MAO B inhibitors
Alcohol dehydrogenase I Ethanol Alcohol dehydrogenase inhibitor
Alcohol dehydrogenase I Fomepizole Alcohol Dehydrogenase inhibitor

80. 80
Summary: System-wise Drugs acting on Enzymes
CNS (continued)
Class Drugs Mechanism
Aldehyde Dehydrogenase I Disulfiram Aldehyde Dehydrogenase inhibitor
Antiepileptic drugs Valproate GABA Transaminase inhibitor
Antiepileptic Vigabatrin GABA Transaminase inhibitor
Peripheral decarboxylase I Carbidopa DOPA decarboxylase inhibitor
Antiparkinsonian COMT I Tolcapone, Entacapone COMT inhibitors

81. 81
Summary: System-wise Drugs acting on Enzymes
Haematology
Class Drugs Mechanism
Parenteral anticoagulants Heparin AT IIi activator
Coumarin derivatives Warfarin Vitamin K reductase inhibitors
Fibrinolytic Drugs Streptokinase, Urokinase Tissue type Plasminogen activators
Platelet Phosphodiesterase
inhibitors
Dipyridamol, Cilostazol Phosphodiesterase III inhibitors

82. 82
Summary: System-wise Drugs acting on Enzymes
Antibacterials
Class Drugs Mechanism
β-lactam antibiotic Penicillins
Bacterial Transpeptidase
inhibitors
β-Lactamase inhibitors Clavulanic acid, Sulbactam β-Lactamase inhibitors
Fluoroquinolones ciprofloxacin, gemifloxacin Topoisomerase DNA Gyrase
Rifamycins Rifampicin, Rifabutin Prokaryotic RNA Polymerase inhibitor
Sulfonamides sulfamethoxazole, Sulfadiazine
Dihydropteroate Synthase
inhibitors

83. 83
Summary: System-wise Drugs acting on Enzymes
Antifungals
Class Drugs Mechanism
Imidazoles Ketoconazole, Miconazole
14-α-sterol demethylase
inhibitor
Echinocandins Caspofungin, Micafungin
1,3-β-d-Glucan synthase
inhibitor
Allylamines Terbinafine Squalene Epoxidase Inhibitor

84. 84
Summary: System-wise Drugs acting on Enzymes
Antivirals (Non Retroviral)
Class Drugs Mechanism
Anti Herpesvirus agents Acyclovir, Valacyclovir
Viral DNA polymerase
inhibitor
Anti Herpesvirus agents Ganciclovir, Valganciclovir
Viral Phosphotransferase
inhibitor
Antiinfluenza Oseltamivir, Zanamivir
Influenza Neuramidase
inhibitor
Anti Hepatitis B drugs Entecavir, Adefovir
Viral DNA polymerase
inhibitor
Anti Hepatitis C drugs Sofosbuvir
HCV RNA Polymerase
inhibitor
Anti Hepatitis C drugs Simeprevir HCV NS3 Protease inhibitor

85. 85
Summary: System-wise Drugs acting on Enzymes
Antiretrovirals
Class Drugs Mechanism
Nucleoside RTI Zidovudine, Lamivudine
Viral Reverse Transcriptase
inhibitor
Nucleotide RTI Tenofovir
Viral Reverse Transcriptase
inhibitor
Non Nucleoside RTI Nevirapine, Efavirenz
HIV 1 Reverse Transcriptase
inhibitors
Protease Inhibitors
Saquinavir, Ritonavir,
Lopinavir
Virus aspartyl Protease
Inhibitor
Integrase Inhibitors Raltegravir, Elvitegravir HIV encoded Integrase

86. 86
Summary: System-wise Drugs acting on Enzymes
Antiprotozoal
Class Drugs Mechanism
Antiprotozoal drugs Eflornithine
Ornithine decarboxylase
inhibitor

87. 87
Summary: System-wise Drugs acting on Enzymes
Anticancer drugs
Class Drugs Mechanism
Antimetabolites Methotrexate, Pemetrexed DHFR inhibitors
Pyrimidine Analogues 5-FU, Floxuridine Thymidylate synthase inhibitors
Pyrimidine Analogues Cytarabine DNA polymerase inhibitors
Antibiotic anticancer drugs Bleomycin, Dactinomycin Topoisomerase II inhibitors
Epipodophyllotoxins Etoposide, Teniposide Topoisomerase II inhibitors
Camptothecins Topotecan, Irinotecan Topoisomerase I inhibitors
Misc. anticancer drugs Hydroxyurea Ribonucleotide Reductase
Proteosome Inhibitors Bortezomib, Carfilzonib Proteosome Inhibitors
Histone Deacetylase I Vorinostat Histone Deacetylase Inhibitors

88. 88
Summary: System-wise Drugs acting on Enzymes
Signalling Pathways
Mechanism Drug Mechanism
Monoclonal antibody EGFR
kinase inhibitors
Cetuximab, Necitumumab EGFR Kinase inhibitors
Small molecule EGFR Kinase
Inhibitor
Erlotinib, Gefitinib, Afatinib EGFR Kinase Inhibitors
Small molecule HER2 Kinase
inhibitors
Lapatinib, Neratinib
HER2 Kinase inhibitors
EGFR inhibitors
Monoclonal Antibody HER2
Kinase inhibitors
Trastuzumab, Pertuzumab HER2 Kinase inhibitors
Platelet derived growth factor
inhibitors
Olaratumab
Platelet derived growth factor
inhibitors
Mutant B-RAF Kinase
Inhibitors
Vemurafenib, Dabrafenib
Mutant B-RAF Kinase
Inhibitors

89. 89
Summary: System-wise Drugs acting on Enzymes
Signalling Pathways (continued)
Mechanism Drug Mechanism
MAP Kinase Inhibitors Cobimetinib, Trametinib MAP Kinase Inhibitors
Cyclin dependent kinase 4/6
inhibitors
Palbociclib, Abemaciclib
Cyclin dependent kinase 4/6
inhibitors
Anaplastic lymphoma kinase
inhibitors
Alectinib, Ceritinib
Anaplastic lymphoma kinase
inhibitors
VEGF inhibitor Bevacizumab, Ramucirumab VEGF inhibitor
Bruton Tyrosine Kinase
inhibitors
Ibrutinib
Bruton Tyrosine Kinase
inhibitors
PI3K inhibitors Idelalisib
Phosphotidylinositol-4,5-
Biphosphate-3 K inhibitors

90. 90
Summary: System-wise Drugs acting on Enzymes
Immunomodulators
Class Drugs Mechanism
Lymphocyte signalling I Cyclosporine, Tacrolimus Calcineurin Inhibitors
Lymphocyte signalling I Sirolimus, Everolimus mTOR inhibitors
Antimetabolites Mycophenolate Mofetil IMP Dehydrogenase II Inhibitors
Immune cell Adhesion I Natalizumab Alpha-4-integrins inhibitor

91. 91
Newly Approved Drugs
Generic Name Date Mechanism Treatment
upadacitinib August 16, 2019
Janus kinase 1 (JAK)
inhibitor
Rheumatoid
Arthritis
fedratinib August 16, 2019
highly selective JAK2
inhibitor
Myelofibrosis
entrectinib August 15, 2019
selective tyrosine kinase
inhibitor
ROS 1 positive
NSCLC
pexidartinib August 2, 2019 tyrosine kinase inhibitor
Tenosynovial Giant
Cell Tumor
bevacizumab-bvzr June 27, 2019 VEGF inhibitor
multiple types of
cancer
alpelisib May 24, 2019 kinase inhibitor
Postmenopausal
women, and men,
with HR positive,
HER2-negative,
breast cancer.
New FDA Approved Drugs for 2019 | CenterWatch [Internet]. Centerwatch.com. 2019 [cited 2 September 2019]. Available from: https://
www.centerwatch.com/drug-information/fda-approved-drugs/

92. Conclusion
92
• There have been many advancements since enzymes were
first discovered in 1833.
• They are used in various industries & especially for drug
design because altering enzyme activity has immediate &
defined targets.
• Enzymes can be inhibited competitively, non competitively &
uncompetitively or be activated by drugs.
• Microsomal enzymes can also be used as drug targets.
• Transmembrane receptors linked to enzymes are currently
the most explored drug targets since they play an important
role in the fields of oncology & immunology.

93. References
93
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94. References (continued)
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and its pharmacological consequences. Trends in pharmacological sciences. 1991 Jan 1;12:297-303.
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Available from: https://www.centerwatch.com/drug-information/fda-approved-drugs/

95. 95