1. METABOLIC BLOCKER IN DRUG DESIGN
BY KHUSHWANT RAVI THORAT
GUIDED BY DR. SUSHMA GHADIGAONKAR
Designed by Khushwant Thorat

2. DO YOU KNOW
• Medicine in 21st century has become the science in
which metabolic blockers are directed against macro
molecules.
• Metabolic blocker posses position in biological
macromolecule that can be used as good drug target.
Designed by Khushwant Thorat

3. DO YOU KNOW
• Survey reported in 2002 found that 30% of
all the drug in clinical use derived
therapeutic efficacy by blocking metabolic
enzymes.
• Then it was updated in 2007 and found that
47% of newly launched drug all marketed
small molecule drug inhibit the enzyme and
their molecular target.
Designed by Khushwant Thorat

4. METABOLIC BLOCKER
• Metabolic blocker are the substance which
block the biosynthetic pathway due to a
genetic enzyme defect or inhibition of an
enzyme by drug or other substances.
• It can be exploited by correcting deficiency
or excess by inhibiting the enzyme.
Designed by Khushwant Thorat

5. SEIZURE
• It can be caused by insufficient GABA. So
thus inhibition of GABA transferase enzyme
we can increase the conc. of GABA
ultimately production of anticonvulsant
effect.
Designed by Khushwant Thorat

6. GOUT
• In Gout, there is excess production of uric
acid which can be treated by inhibiting the
enzyme Xanthine oxidase.
Designed by Khushwant Thorat

7. Compound Target enzyme Clinical use
Acetazolamide Carbonic anhydrase Glaucome
Acyclovir Viral DNA polymerase Herpes
Allopurinol Xanthine oxidase Gout
Aspirin COX Inflammation, pain,
fever
Amoxicilin Penicillin binding
protein
Bacterial infections
Enalapril Angiotensin converting
enzyme
Hypertension
Designed by Khushwant Thorat

8. Compound Target enzyme Clinical use
Carbidopa Dopa decarboxylase Parkinson’s disease
Digoxin Sodium potassium
ATPase
Heart disease
Lovastatin HMG- CoA reductase Cholesterol lowering
Methotrexate Dihydrofolate
reductase
Cancer,
immunosuppression
Norfloxacin DNA gyrase Urinary tract infection
Omeprazole H⁺,K⁺ ATPase Peptic ulcer
Viagra Phosphodiesterase Erectile dysfunction
Designed by Khushwant Thorat

9. ENZYME INHIBITOR
Non specific
Denaturation
Acid, base, temperature,
heavy metal
Specific
Reversible
Competitive
Non
competitive
uncompetitive
Irreversible
Designed by Khushwant Thorat

10. Competitive (reversible) inhibitors
• Inhibitor binds reversibly to the active site
• Intermolecular bonds are involved in binding
• No reaction takes place on the inhibitor
• Inhibition depends on the strength of inhibitor binding and
inhibitor concentration
• Substrate is blocked from the active site
• Increasing substrate concentration reverses inhibition
• Inhibitor likely to be similar in structure to the substrate
• Example: Disulfiram
I
EE
S
I
E
Designed by Khushwant Thorat

11. Non competitive (irreversible) inhibitors
• Inhibitor binds irreversibly to the active site
• Covalent bond formed between the drug and the enzyme
• Substrate is blocked from the active site
• Increasing substrate concentration does not reverse inhibition
• Inhibitor likely to be similar in structure to the substrate
• Example: Nifedipine
X
OH OH
X
O
Covalent Bond
Irreversible inhibition
Designed by Khushwant Thorat

12. ACTIVE SITE
(open)
ENZYMEEnzyme
Non competitive (reversible) allosteric inhibitors
• Inhibitor binds reversibly to the allosteric site
• Intermolecular bonds are formed
• Induced fit alters the shape of the enzyme
• Active site is distorted and is not recognised by the substrate
• Increasing substrate concentration does not reverse inhibition
• Inhibitor is not similar in structure to the substrate
Example: Penicillin
Allosteric
site
Active site
(open)
ENZYMEEnzyme
Induced
fit
Active site
unrecognisable
Allosteric
inhibitor
Designed by Khushwant Thorat

13. Non competitive (reversible) allosteric inhibitors
• Enzymes with allosteric sites often at start of biosynthetic
pathways
• Enzyme is controlled by the final product of the pathway
• Final product binds to the allosteric site and switches off
enzyme
• Inhibitor may have a similar structure to the final product
• Example: Penicillin
P’’’P’’P’
Biosynthetic pathway
Feedback controlInhibition
PS
(open)
ENZYMEEnzyme
Designed by Khushwant Thorat

14. Designed by Khushwant Thorat