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DESIGN OF ENZYME

INHIBITORS AS DRUGS
By : Ms.Tabhitha K
Guide : Mr. Sampath Ayyappa G, M.Pharm

ENZYMES - INTRODUCTION

Uncompetitive reversible inhibitors . Irreversible inhibitors • Reversible enzyme inhibitors can be classified into three categories: 1. Non-competitive reversible inhibitors and 3. Competitive reversible inhibitors 2.ENZYME INHIBITION • Enzyme inhibitors can be grouped into two general categories: 1. Reversible inhibitors 2.

Slow. Alternative substrate inhibition 3.P E + P Kinetic scheme for competetive enzyme inhibition • There are four different approaches to the design of competitive reversible inhibitors: 1. Kon E + I . Transition state analog inhibition and 4. E I Koff +S -S E . tight – binding inhibition .S E . Simple competitive inhibition 2.

... blood vessel s) C-terminal His Leu (dipeptide) ACE / dipeptidyl carboxypeptidase I Asp Arg Val Tyr Ile His Pro Phe aminopeptidase A Asp Angiotensin II (octapeptide) aminopeptidase N aminopeptidase A Asp Arg Asp aminopeptidase N ACE Val Tyr Ile His Pro Phe Arg Val Tyr Ile His Pro Phe Arg Val Tyr Ile His Pro Phe His Leu Arg His Leu Angiotensin IV Angiotensin III (hexapeptide) Renin-angiotensin system . (hydrolysi s) Asp Arg Val Tyr Ile His Pro Phe His Leu Angiotensin I (decapeptide) (lungs. DESIGN OF SIMPLE COMPETITIVE INHIBITORS Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn . Angiotesinogen (human liver) renin (proteolytic enzyme) Val Ile His Asn ..

OH - R2' O R1' O R1" O R2" - N C C N C C N C C N C COO H H H H H H H H Function of the Zn(II) cofactor in ACE catalysis S1" --- -- S1' 2+ Zn -. carboxypeptidase A O N C C N C C substrate H H H H O --- --. -- R O CH2 . --- --. --- -. -- -. -- -. + -- -. 2+ Zn . -- CH2 O O C C C C (R)-2-benzylsuccinic O H2 H O acid Hypothetical active site of carboxypeptidase A . - --.

S1" --- -- S1' --. 2+ --- Zn + -- R O CH2 O products of N C C H2N C C hydrolysis H H O H O CH2 O O (R)-2-benzylsuccinic C C C C O H2 H acid O The collected products hypothesis of enzyme inhibition .

--. -- -- .N -- O H2 H --. - HS N --. -- -. +-- --. --- . . -. . . --. --- H . --. --- --. --. O --. R2' O . --. --. --. . H --- ACE --. --. --. - R3' O R2' O O N C N C N substrate H H H H --. --. . . B S2' S1 2+ S1' Zn --. O --. --- - O R2' O O C C carboxyalkylproline --. --- H3C --- . --. --. O mercaptoalkylproline S C C N O H2 H O CO2H Captopril Hypothetical binding of carboxyalkylproline and mercaptoalkylproline derivatives to ACE .-. --. .

S1 Hypothetical interactions of enalaprilat with ACE B S2' S1' ZnII H + ACE CH2 CH3 O O O H N C N N Substrate (peptide) H H H O CH2 CH3 O O O N C H N Product H2N H H O O O O CH2 CH3 O O H C N N Enalaprilat H2 H O .

CH2 CH2 H2C H3C esterase H2C CH3 H H H H N N H2CH3COOC N HOOC N H H O O CO2H CO2H Enalapril (prodrug) Enalaprilat CH2 NH2 H2C (CH2)4 CO2H H R N N H O CO2H Lisinopril .

DESIGN OF ALTERNATIVE SUBSTRATE INHIBITORS NH2 H2N N H2N SO2NH2 N SO2NH2 Sulfanilamide Prontosil dihydropteroate diphosphate + p-amino benzoic acid dihydropteroate synthase sulfonamides dihydropteroate dihydrofolate dihydrofolate reductase trimethoprim tetrahydrofolate Biosynthesis of bacterial folic acid .

H H2N N N O O N O P O P O N O O OH dihydropteroate diphosphate O H2N SO2NH2 dihydropteroate synthase H2N O sulfanilamide PABA H H2N N N H H2N N N N N O N OH N N H O OH N SO2NH2 dihydropteroate H produces tetrahydrofolate for the biosynthesis of purines inhibits tetrahydrofolate biosynthesis .

DESIGN OF TRANSITION STATE ANALOGS 2+ Zn 2+ **1 Zn 2+ R1' O Zn R1" R1' O R1" N C C NC NC C NC R1' O R1" H H HH HH HH NC C NC O O HH HH H H O H H H H B B B + -O Ph O CH3O CH2 C C C N C C Pro H2 H H Enalaprilat 2+ **2 2+ Zn Zn R1' O R1" R1' O R1" -H NC NC C HN C NC C 2 HH H HH H O O H H HB B + -O Ph O CH3O CH2 C C C N C C Pro H2 H H Enalaprilat Hypothetical mechanism for ACE catalyzed peptide hydrolysis .

DESIGN OF MULTISUBSTRATE ANALOGS 2 -OOC PO3 2 -OOC ** -OOC PO 3 O O H + H2N H2N N NH2 COO- O NH2 COO. N-carbamoyl- phosphate acid PO 3 -OOC L-aspartate CH2 O N COO - H PALA N-phosphonoacetyl -L-aspartate Hypothetical mechanism for the reation catalyzed by aspartate transcarbamylase . O COO - O NH2 carbamoyl L-aspartic 2 .

DESIGN OF AFFINITY LABELING AGENTS O H b H H N CO2H Me a S Me O N H R O H H Me Nb CO2H H Me O Na H Peptidoglycan Comparison of the structure of penicillins with acyl D-alanyl-D-alanine  The Na to Nb distances (3. .4 A0 in the penicillins and 5.3 A0) and the Nb to carboxylate carbon distances (2.  The Na to carboxylate carbon distance is 5.5 A0) in both molecules are identical.7 A0 in D-alanyl-D-alanine.

Acylation of peptidoglycan transpeptidase by penicillins .

MECHANISM-BASED ENZYME INACTIVATORS .

the vigabatrin and PLP complex (E) is a potent electrophile. PMP and keto acid (D). . Sabril) is the first rationally designated mechanism-based inactivator drug . • In the case of normal substrate turnover. an Anticonvulsant Drug • 4-Amino-5-hexenoci acid (vigabatrin.• Vigabatrin. • However. a Michael acceptor. which can undergo conjugate addition by an active site nucleophile (x-) and produce inactivated enzyme (F or G). (A). • The same hydrolysis could occur with vigabatrin and PLP complex (E) to give the corresponding products. hydrolysis of the complex of PLP and aminoacid gives pyridoxamine 5’-phosphate (PMP) and the keto acid.

Hypothetical mechanism for inactivation of GABA aminotransferase by Vigabatrin .

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