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Metabolic blocker
- 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