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APPROACHES TO THE RATIONAL DESIGN
      OF ENZYME INHIBITORS


          Submitted by :Manju Abraham
          Department : Pharma chemistry.
                       1st year
CONTENTS
•   Introduction
•   Definition and description of enzyme
•   International classification of enzymes
•   Enzyme inhibition
•   Classification of enzyme inhibitors
•   Mechanism of enzyme inhibition
•   Enzyme inhibitors in medicine
•   Enzyme inhibitors in basic research
INTRODUCTION

 Historically , compounds that were extracted from natural
  products have been used as medicinal agents .
 Subsequently , they have been shown to have their
  therapeutic effect by targeting certain systemic enzymes .
 e.g. bark of the willow tree (anti-pyretic and analgesic
  effects )



 Another e.g. is physostigmine , an inhibitor of
  acetycholinesterase .
 In 20th century , the concept of the “MAGIC BULLET”having
  selective toxicity , was introduced by Ehrlich as a rational
  approach to chemotherapy .
 The discovery in 1935 of the antibacterial activity of the
  azodye prontosil by Domagk , and subsequent explanation
  in 1940 by Woods of its metabolic reduction to
  sulfanilamide --------finally paved the way .
 These strategies use :
1. Sophisticated assays ,
2. enzyme crystal structures and active site environments ,
3. site-directed mutagenesis experiments of catalytic
   residues of enzymes , and
4. molecular docking experiments employing computers .
ENZYMES
  Enzymes are soluble ,colloidal ,organic catalysts ,formed by
  living cells specific in action ,protein in nature ,inactive at
  zero degree celsius and destroyed by moist heat at 100
  degree celsius .

DESCRIPTION :
 Enzymes are the specialised proteins which catalyze various
  biochemical reactions .
 The concept of enzyme inhibition is routinely utilized to
  affect biosynthesis and metabolic pattern of various
  hormones ,autocoids , and neurotransmitters .
 In 1926 , J.B.Sumner have isolated urease .
    Each enzyme is assigned with ,
1.   a recommended name ,
2.   a systemic name ,
3.   a classification number .
INTERNATIONAL CLASSIFICATION OF ENZYMES

1) Oxido-reductases :
   Enzymes which catalyze oxidoreductions between two
   substrates e.g. A and B.
         Areduced + Boxidised   =   Aoxidised   +   Breduced
   classic e.g. Include succinic dehydrogenase , cytochrome
   oxidase .

2) Transferases :
    They catalyze the transfer of some group or radical ,R,
   from one molecule A ,to another B. e.g. transfer of a
   phosphate between ATP and a sugar molecule.
3) Hydrolases :
   These enzymes have the ability to induce hydrolysis of esters ,acid
   anhydrides, glycosidic bonds, peptide bonds and other
   bonds , e.g. esterases.

4) Lyases:
    Enzymes which catalyze the formation or addition of double bonds .
   e.g. hydratase .

5) Isomerases :
    Enzymes catalyzing interconversion of optical, geometrical , or
   positional isomers .
   e.g .mutarotation of glucose by mutases .

6) Ligases :
    Enzymes which catalyze joining of two substrates at the expense of
   energy , also referred to as synthetases.
ENZYME INHIBITION
o Inhibition of a biochemical pathway will be most effective if
  the drugs act on the rate-limiting step .
   e.g. the conversion of tyrosine to dopa .

o The rate limiting step in a biochemical pathway is not always
  possible to block .

o This results into an increase in the turnover in the sequence
  of steps located before the enzyme blocked .

o The net outcome is an accumulation of the intermediate
  product (substrate ).

o As a consequence ,the inhibitor will be displaced from the
  enzyme surface by the substrate thus accumulated.
CLASSIFICATION OF ENZYME INHIBITORS

• The inhibition of a suitably selected target enzyme leads
  to build up in concentration of substrates and a
  corresponding decrease in the concentration of the
  metabolites .
• Important parameters for selecting an enzyme inhibitor
  are :
1. Biochemical environment of the target enzyme ,
2. Specificity of action ,
3. The time period for which an enzyme is blocked .
 Various clinically used enzyme inhibitors may be broadly
  categorised in to :

a) Reversible enzyme-inhibitors , and
b) Irreversible enzyme-inhibitors .

    REVERSIBLE ENZYME- INHIBITORS
   Inhibitors may further be categorised into ,
1. Competitive inhibitor
2. Uncompetitive inhibitor
3. Non-competitive inhibitor
COMPETITIVE INHIBITION :
• The inhibitor reacts reversibly with an enzyme to form an
  enzyme-inhibitor complex .




• The inhibitor must possess structural similarity with the natural
  substrate to act as competitive enzyme inhibitor .

    UNCOMPETITIVE INHIBITION :
• The inhibitor combines with enzyme-substrate complex rather
  than with the free enzyme to give inactive enzyme inhibitor
  complex.
NON-COMPETITIVE INHIBITOR :

•   A non-competitive inhibitor can combine with either the
    free enzyme or the enzyme-substrate complex , interfering
    with the action of both .

•   Deforms the shape of enzyme .

•   The altered shape and conformation of the enzyme slow
    down both , the rates of formation and dissociation of
    enzyme-substrate complexes .
• DRAWBACKS :

 Loss of potency .

The reasons behind this loss in potency include

a) Because of invivo metabolism ,

b) The rate-controlling step in the metabolic chain need not
   to be always catalysed by the target enzyme .

a) A required concentration of the drug does not always
   built up at target sites .
MECHANISMS OF ENZYME INHIBITION

• The different ways of enzyme inhibition are as follows :
1. The blockade of an enzyme , catalysing a particular
   biochemical reaction leads to accumulation of the
   substrate. This results into a desired biological response .
2. The inhibition of an enzyme that catalyses the rate-
   limiting step decreases the production of a metabolite .




          (Multistep biochemical pathway)

3. Most of the enzymes need co-factors to catalyse the
   biochemical pathway . Inhibitors can be developed
   selectively for the co-factor involved .
4. Two inhibitors may be employed simultaneously to achieve
   a great therapeutic effects .
   e.g. co-trimoxazole ( trimethoprim and sulphamethoxazole ).




5. If the metabolism of the end-product is minimised , the
   accumulated end-product decreases the activity of an
   enzyme on its substrate .
6. Inhibition of metabolizing target enzyme permits higher
   plasma levels as well as an increase in the plasma half-life
   of the drug .




e.g. clavulanic acid inhibits beta-lactamase enzymes .
7. Multisubstrate analogs :
   A multisubstrate compound consists the features of
    binding sites of two or more different substrates in the
    same molecule .
   e.g. pyridoxyl alanine has more binding ability towards
    pyruvate transaminase than pyridoxal and alanine .
Pyridoxal alanine
9. Transition state analogs :
   An enzyme interacts with a substrate to form enzyme
   substrate complex through a tetrahedral transition state .




  A transition state analog binds more tightly to an enzyme
  than it does its substrate .
  e.g. penicillin is a transition state analog which binds to the
  peptidoglycan transpeptidase .
PENICILLINS
10. Suicide enzyme inhibitors ( Kcat inhibitors ) :
    Irreversible enzyme inhibitor which utilizes highly
    electrophilic species such as alpha-halogenated carbonyl
    compounds or other strong alkylating agents which inturn
    irreversibly reacts with a nucleophile group on the
    enzyme.
Suicide enzyme inhibitors are the compounds that possess
latent reactive functional groups which are unmasked by
the catalytic action of the enzyme.
 e.g. Inhibition of aldehyde dehydrogenase by
cyclopropanone , a metabolite of coprine .
11. Active site directed irreversible inhibitors :
    This category of inhibitors are designed by two important
    aspects :
a) 1st approach :
    A section of the reactive part of the enzyme may be
    incorporated into the inhibitor to recognize and to direct
    the inhibitor molecule to the enzyme’s active site .
b) 2nd approach :
    A strong nucleophile is placed in the inhibitor molecule
    which is expected to interact with an electrophile moiety
    located near the active enzyme site .
12. Quinone inhibition of enzymes :
    Quinones can oxidise two SH-groups to form an S-S
    linkage .
ENZYME INHIBITORS IN MEDICINE
• A selective inhibitor may block either a single enzyme or a
   group of enzymes .
• This will result in either a decrease in the concentration of
   enzymatic products or an increase in the concentration of
   enzymatic substrates .
• The effectiveness of an enzyme inhibitor as a therapeutic
   agent will depend on ,
a. The potency of the inhibitor ,
b. Its specificity ,
c. The choice of a metabolic pathway ,
d. The inhibitor or a derivative possessing appropriate
    , pharmacokinetic characteristics .
• Low dosage and high specificity combine to reduce the
  toxicity problems .

• High specificity can avoid depletion of the inhibitor
  concentrations in the host by non-specific pathways .

• Good bioavailability of the drug is also important .

• Two types of approaches to facilitate the transport of
  enzyme inhibitors into the cell include :
          1. physical approaches ,
          2. chemical approaches .
{Examples of enzyme inhibitors used in the treatment of
bacterial,fungal ,viral and parasite diseases }
CLINICAL USE           ENZYME INHIBITED          INHIBITOR
Antibacterial          Dihydrofolate reductase   Trimethoprim ,
                                                 methotrexate
Antibacterial          Alanine racemase          D-cycloserine
Antifungal             Fungal squalene -         Terbinafine , naftifine
                       expoxidase
Antiviral              DNA, RNA polymerases      Cytosine arabinoside
Antiviral              Viral DNA polymerase      Acyclovir ,vidarabine
antiprotozoal          Ornithine decarboxylase   Alpha-difluoromethyl
                                                 ornithine
• Beta – lactamases are bacterial enzymes which is an
  important target for drug design .
• Inhibitors of beta-lactamases include clavulanic acid and
  sulbactam (penicillanic acid sulfone ) .




• Act to prevent the bacterial degradation of penicillins and
  cephalosporins by beta-lactamases , thereby extending their
  life-time and effectiveness .
EXAMPLES OF ENZYME INHIBITORS USED IN THE
                 TREATMENT OF CANCER




TYPE OF CANCER             ENZYME INHIBITED            INHIBITOR
Benign prostatic           Steroid 5 alpha-reductase   Finasteride
hyperplasia
Estrogen mediated breast   Aromatase                   Aminoglutethimide
cancer
Colorectal cancer          Thymidylate synthase        5-fluorouracil
Small-cell lung cancer ,   Topoisomerase ii            Etoposide
non-Hodgkin’s lymphoma
Hairy-cell leukemia        Adenosine-deaminase         pentostatin
• SIDE EFFECTS :
1. Rapidly dividing normal cells, such as hair follicles , the
   cells lining the GIT , and the bone marrow cells involved
   in the immune system are also significantly affected .

2. The resultant nausea ,hair loss , and susceptibility to
   infection means that this type of chemotherapy is seldom
   employed as a first line defence against cancer .
EXAMPLES OF ENZYME INHIBITORS USED IN VARIOUS HUMAN
                     DISEASE STATES

CLINICAL USE        ENZYME INHIBITED    INHIBITOR
Epilepsy            GABA transaminase   Gama- vinyl GABA
Antidepressant      MAO                 Tranylcypromine ,
                                        phenelzine
Antihypertensive    ACE                 Captopril, enalaprilat
Cardiac disorders           -ATPase     Cardiac glycosides
Gout                Xanthine oxidase    Allopurinol
Ulcer                  ,   - ATPase     omeprazole
• A variety of diseases may be treated by the inhibition of
  an individual enzyme or by using enzyme inhibitors to
  regulate the metabolite concentration in the body .

• For e.g. an imbalance of the two neurotransmitters ,
  glutamate and gama-aminobutyric acid , is responsible for
  the convulsions observed in epileptic seizure .

• This led to the development of the GABA-T inhibitor ,
  vigabatrin .
• The statins , a group of serum cholesterol lowering drugs
  , are inhibitors of HMG-CoA reductase .

• Catalyses the irreversible conversion of HMG-CoA to
  mevalonic acid (rate-determining step ) .

• Inhibitors such as simvastatin----------hyperlipidemia and
  hypercholesteremia .
ENZYME INHIBITORS IN BASIC RESEARCH
• Enzyme inhibitors have found a multitude of uses :
1. As useful tools for the elucidation of structure and
   function of enzymes .
2. As probes for chemical and kinetic processes and in the
   detection of short-lived reaction intermediates .
3. Product inhibition patterns provide information about an
   enzymes kinetic mechanism and the order of substrate
   binding .
4. Covalently binding enzyme inhibitors have been used to
   identify active-site amino acid residues .
5. Reversible enzyme inhibitors are used to facilitate enzyme
   purification .
6. Immobilized enzyme inhibitors can also be used to
   identify their intracellular targets whereas irreversible
   inhibitors can be used to localize and quantify enzymes
   invivo .
REFERENCES
1. Drug design , by Dr.V.M.Kulkarni and Dr.K.G.Bothara ,4th
   edition , page no:25-31 .
2. Medicinal chemistry and drug discovery ,by Burger , 6th
   edition ,1st volume , page no :716-720.
THANK YOU

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Enzyme inhibitors

  • 1. APPROACHES TO THE RATIONAL DESIGN OF ENZYME INHIBITORS Submitted by :Manju Abraham Department : Pharma chemistry. 1st year
  • 2. CONTENTS • Introduction • Definition and description of enzyme • International classification of enzymes • Enzyme inhibition • Classification of enzyme inhibitors • Mechanism of enzyme inhibition • Enzyme inhibitors in medicine • Enzyme inhibitors in basic research
  • 3. INTRODUCTION  Historically , compounds that were extracted from natural products have been used as medicinal agents .  Subsequently , they have been shown to have their therapeutic effect by targeting certain systemic enzymes .  e.g. bark of the willow tree (anti-pyretic and analgesic effects )  Another e.g. is physostigmine , an inhibitor of acetycholinesterase .  In 20th century , the concept of the “MAGIC BULLET”having selective toxicity , was introduced by Ehrlich as a rational approach to chemotherapy .
  • 4.  The discovery in 1935 of the antibacterial activity of the azodye prontosil by Domagk , and subsequent explanation in 1940 by Woods of its metabolic reduction to sulfanilamide --------finally paved the way .  These strategies use : 1. Sophisticated assays , 2. enzyme crystal structures and active site environments , 3. site-directed mutagenesis experiments of catalytic residues of enzymes , and 4. molecular docking experiments employing computers .
  • 5. ENZYMES Enzymes are soluble ,colloidal ,organic catalysts ,formed by living cells specific in action ,protein in nature ,inactive at zero degree celsius and destroyed by moist heat at 100 degree celsius . DESCRIPTION :  Enzymes are the specialised proteins which catalyze various biochemical reactions .  The concept of enzyme inhibition is routinely utilized to affect biosynthesis and metabolic pattern of various hormones ,autocoids , and neurotransmitters .  In 1926 , J.B.Sumner have isolated urease .
  • 6. Each enzyme is assigned with , 1. a recommended name , 2. a systemic name , 3. a classification number .
  • 7. INTERNATIONAL CLASSIFICATION OF ENZYMES 1) Oxido-reductases : Enzymes which catalyze oxidoreductions between two substrates e.g. A and B. Areduced + Boxidised = Aoxidised + Breduced classic e.g. Include succinic dehydrogenase , cytochrome oxidase . 2) Transferases : They catalyze the transfer of some group or radical ,R, from one molecule A ,to another B. e.g. transfer of a phosphate between ATP and a sugar molecule.
  • 8. 3) Hydrolases : These enzymes have the ability to induce hydrolysis of esters ,acid anhydrides, glycosidic bonds, peptide bonds and other bonds , e.g. esterases. 4) Lyases: Enzymes which catalyze the formation or addition of double bonds . e.g. hydratase . 5) Isomerases : Enzymes catalyzing interconversion of optical, geometrical , or positional isomers . e.g .mutarotation of glucose by mutases . 6) Ligases : Enzymes which catalyze joining of two substrates at the expense of energy , also referred to as synthetases.
  • 9. ENZYME INHIBITION o Inhibition of a biochemical pathway will be most effective if the drugs act on the rate-limiting step . e.g. the conversion of tyrosine to dopa . o The rate limiting step in a biochemical pathway is not always possible to block . o This results into an increase in the turnover in the sequence of steps located before the enzyme blocked . o The net outcome is an accumulation of the intermediate product (substrate ). o As a consequence ,the inhibitor will be displaced from the enzyme surface by the substrate thus accumulated.
  • 10. CLASSIFICATION OF ENZYME INHIBITORS • The inhibition of a suitably selected target enzyme leads to build up in concentration of substrates and a corresponding decrease in the concentration of the metabolites . • Important parameters for selecting an enzyme inhibitor are : 1. Biochemical environment of the target enzyme , 2. Specificity of action , 3. The time period for which an enzyme is blocked .
  • 11.  Various clinically used enzyme inhibitors may be broadly categorised in to : a) Reversible enzyme-inhibitors , and b) Irreversible enzyme-inhibitors . REVERSIBLE ENZYME- INHIBITORS Inhibitors may further be categorised into , 1. Competitive inhibitor 2. Uncompetitive inhibitor 3. Non-competitive inhibitor
  • 12. COMPETITIVE INHIBITION : • The inhibitor reacts reversibly with an enzyme to form an enzyme-inhibitor complex . • The inhibitor must possess structural similarity with the natural substrate to act as competitive enzyme inhibitor . UNCOMPETITIVE INHIBITION : • The inhibitor combines with enzyme-substrate complex rather than with the free enzyme to give inactive enzyme inhibitor complex.
  • 13. NON-COMPETITIVE INHIBITOR : • A non-competitive inhibitor can combine with either the free enzyme or the enzyme-substrate complex , interfering with the action of both . • Deforms the shape of enzyme . • The altered shape and conformation of the enzyme slow down both , the rates of formation and dissociation of enzyme-substrate complexes .
  • 14. • DRAWBACKS :  Loss of potency . The reasons behind this loss in potency include a) Because of invivo metabolism , b) The rate-controlling step in the metabolic chain need not to be always catalysed by the target enzyme . a) A required concentration of the drug does not always built up at target sites .
  • 15. MECHANISMS OF ENZYME INHIBITION • The different ways of enzyme inhibition are as follows : 1. The blockade of an enzyme , catalysing a particular biochemical reaction leads to accumulation of the substrate. This results into a desired biological response .
  • 16. 2. The inhibition of an enzyme that catalyses the rate- limiting step decreases the production of a metabolite . (Multistep biochemical pathway) 3. Most of the enzymes need co-factors to catalyse the biochemical pathway . Inhibitors can be developed selectively for the co-factor involved .
  • 17. 4. Two inhibitors may be employed simultaneously to achieve a great therapeutic effects . e.g. co-trimoxazole ( trimethoprim and sulphamethoxazole ). 5. If the metabolism of the end-product is minimised , the accumulated end-product decreases the activity of an enzyme on its substrate .
  • 18. 6. Inhibition of metabolizing target enzyme permits higher plasma levels as well as an increase in the plasma half-life of the drug . e.g. clavulanic acid inhibits beta-lactamase enzymes . 7. Multisubstrate analogs : A multisubstrate compound consists the features of binding sites of two or more different substrates in the same molecule . e.g. pyridoxyl alanine has more binding ability towards pyruvate transaminase than pyridoxal and alanine .
  • 20. 9. Transition state analogs : An enzyme interacts with a substrate to form enzyme substrate complex through a tetrahedral transition state . A transition state analog binds more tightly to an enzyme than it does its substrate . e.g. penicillin is a transition state analog which binds to the peptidoglycan transpeptidase .
  • 21. PENICILLINS 10. Suicide enzyme inhibitors ( Kcat inhibitors ) : Irreversible enzyme inhibitor which utilizes highly electrophilic species such as alpha-halogenated carbonyl compounds or other strong alkylating agents which inturn irreversibly reacts with a nucleophile group on the enzyme.
  • 22. Suicide enzyme inhibitors are the compounds that possess latent reactive functional groups which are unmasked by the catalytic action of the enzyme. e.g. Inhibition of aldehyde dehydrogenase by cyclopropanone , a metabolite of coprine .
  • 23. 11. Active site directed irreversible inhibitors : This category of inhibitors are designed by two important aspects : a) 1st approach : A section of the reactive part of the enzyme may be incorporated into the inhibitor to recognize and to direct the inhibitor molecule to the enzyme’s active site . b) 2nd approach : A strong nucleophile is placed in the inhibitor molecule which is expected to interact with an electrophile moiety located near the active enzyme site .
  • 24. 12. Quinone inhibition of enzymes : Quinones can oxidise two SH-groups to form an S-S linkage .
  • 25. ENZYME INHIBITORS IN MEDICINE • A selective inhibitor may block either a single enzyme or a group of enzymes . • This will result in either a decrease in the concentration of enzymatic products or an increase in the concentration of enzymatic substrates . • The effectiveness of an enzyme inhibitor as a therapeutic agent will depend on , a. The potency of the inhibitor , b. Its specificity , c. The choice of a metabolic pathway , d. The inhibitor or a derivative possessing appropriate , pharmacokinetic characteristics .
  • 26. • Low dosage and high specificity combine to reduce the toxicity problems . • High specificity can avoid depletion of the inhibitor concentrations in the host by non-specific pathways . • Good bioavailability of the drug is also important . • Two types of approaches to facilitate the transport of enzyme inhibitors into the cell include : 1. physical approaches , 2. chemical approaches .
  • 27. {Examples of enzyme inhibitors used in the treatment of bacterial,fungal ,viral and parasite diseases } CLINICAL USE ENZYME INHIBITED INHIBITOR Antibacterial Dihydrofolate reductase Trimethoprim , methotrexate Antibacterial Alanine racemase D-cycloserine Antifungal Fungal squalene - Terbinafine , naftifine expoxidase Antiviral DNA, RNA polymerases Cytosine arabinoside Antiviral Viral DNA polymerase Acyclovir ,vidarabine antiprotozoal Ornithine decarboxylase Alpha-difluoromethyl ornithine
  • 28. • Beta – lactamases are bacterial enzymes which is an important target for drug design . • Inhibitors of beta-lactamases include clavulanic acid and sulbactam (penicillanic acid sulfone ) . • Act to prevent the bacterial degradation of penicillins and cephalosporins by beta-lactamases , thereby extending their life-time and effectiveness .
  • 29. EXAMPLES OF ENZYME INHIBITORS USED IN THE TREATMENT OF CANCER TYPE OF CANCER ENZYME INHIBITED INHIBITOR Benign prostatic Steroid 5 alpha-reductase Finasteride hyperplasia Estrogen mediated breast Aromatase Aminoglutethimide cancer Colorectal cancer Thymidylate synthase 5-fluorouracil Small-cell lung cancer , Topoisomerase ii Etoposide non-Hodgkin’s lymphoma Hairy-cell leukemia Adenosine-deaminase pentostatin
  • 30. • SIDE EFFECTS : 1. Rapidly dividing normal cells, such as hair follicles , the cells lining the GIT , and the bone marrow cells involved in the immune system are also significantly affected . 2. The resultant nausea ,hair loss , and susceptibility to infection means that this type of chemotherapy is seldom employed as a first line defence against cancer .
  • 31. EXAMPLES OF ENZYME INHIBITORS USED IN VARIOUS HUMAN DISEASE STATES CLINICAL USE ENZYME INHIBITED INHIBITOR Epilepsy GABA transaminase Gama- vinyl GABA Antidepressant MAO Tranylcypromine , phenelzine Antihypertensive ACE Captopril, enalaprilat Cardiac disorders -ATPase Cardiac glycosides Gout Xanthine oxidase Allopurinol Ulcer , - ATPase omeprazole
  • 32. • A variety of diseases may be treated by the inhibition of an individual enzyme or by using enzyme inhibitors to regulate the metabolite concentration in the body . • For e.g. an imbalance of the two neurotransmitters , glutamate and gama-aminobutyric acid , is responsible for the convulsions observed in epileptic seizure . • This led to the development of the GABA-T inhibitor , vigabatrin .
  • 33. • The statins , a group of serum cholesterol lowering drugs , are inhibitors of HMG-CoA reductase . • Catalyses the irreversible conversion of HMG-CoA to mevalonic acid (rate-determining step ) . • Inhibitors such as simvastatin----------hyperlipidemia and hypercholesteremia .
  • 34. ENZYME INHIBITORS IN BASIC RESEARCH • Enzyme inhibitors have found a multitude of uses : 1. As useful tools for the elucidation of structure and function of enzymes . 2. As probes for chemical and kinetic processes and in the detection of short-lived reaction intermediates . 3. Product inhibition patterns provide information about an enzymes kinetic mechanism and the order of substrate binding . 4. Covalently binding enzyme inhibitors have been used to identify active-site amino acid residues . 5. Reversible enzyme inhibitors are used to facilitate enzyme purification .
  • 35. 6. Immobilized enzyme inhibitors can also be used to identify their intracellular targets whereas irreversible inhibitors can be used to localize and quantify enzymes invivo .
  • 36. REFERENCES 1. Drug design , by Dr.V.M.Kulkarni and Dr.K.G.Bothara ,4th edition , page no:25-31 . 2. Medicinal chemistry and drug discovery ,by Burger , 6th edition ,1st volume , page no :716-720.