ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
Peptidomimetics are compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space and which retain the ability to interact with the biological target and produce the same biological effect.
Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide for example
Stability against proteolysis (duration of activity)
Poor bioavailability.
Receptor selectivity or potency (often can be substantially improved).
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
Active constituent of drugs used in diabetic therapyAkshay Kank
In this slide the active constituents which is isolated from herbal sources used for to treat the type 1 and type 2 diabetes is covered. 'Gymnema' and 'swerita chirata' herbal plant is also covered in the slide.This work help in to focus the herbal emphasis on diabetes.
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
The content includes the general introduction of enzymes their basic classification. Enzyme kinetics is described with a short view of Michaelis menten constants. Factors affecting the kinetics of enzymes are also discussed. Principles of enzyme inhibition are discussed with a few examples.
The contents is prepared by the help of books, internet sources, as well as other presentations. I am thankful to all of you.
ENZYME INHIBITION MORE INTERESTING IN CHEMISTRY WAYShikha Popali
WHAT ARE EWNZYMES? HERE IT IS EXPLAIN WITH ITS KINETICS AND LATER ENZYME INHIBITION. WHERE IT ALSO INCLUDES THE CLASSIFICATION OF ENZYME INHIBITORS, AVAILABLE IN MEDICINE WITH ITA BASIC REASEARCH.
Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
Presented by Shikha Popali and Harshpal singh Wahi students from Gurunanak college of pharmacy, Nagpur in Department of pharmaceutical Chemistry. The explained topic is seful for every chemistry student and for others too
Peptidomimetics are compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space and which retain the ability to interact with the biological target and produce the same biological effect.
Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide for example
Stability against proteolysis (duration of activity)
Poor bioavailability.
Receptor selectivity or potency (often can be substantially improved).
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
Active constituent of drugs used in diabetic therapyAkshay Kank
In this slide the active constituents which is isolated from herbal sources used for to treat the type 1 and type 2 diabetes is covered. 'Gymnema' and 'swerita chirata' herbal plant is also covered in the slide.This work help in to focus the herbal emphasis on diabetes.
Contents includes at least three strategies of synthesis for each of three, four, five and six membered heterocylic ring with one or two heteroatoms. One mechanism described out of the three strategies. Few name reactions are described and the other are simple synthetic methods. This presentation was prepared for the partial fulfillment of Master of Pharmacy. The content was taken from the various books, mentioned in slide with the title of references.
The content includes the general introduction of enzymes their basic classification. Enzyme kinetics is described with a short view of Michaelis menten constants. Factors affecting the kinetics of enzymes are also discussed. Principles of enzyme inhibition are discussed with a few examples.
The contents is prepared by the help of books, internet sources, as well as other presentations. I am thankful to all of you.
ENZYME INHIBITION MORE INTERESTING IN CHEMISTRY WAYShikha Popali
WHAT ARE EWNZYMES? HERE IT IS EXPLAIN WITH ITS KINETICS AND LATER ENZYME INHIBITION. WHERE IT ALSO INCLUDES THE CLASSIFICATION OF ENZYME INHIBITORS, AVAILABLE IN MEDICINE WITH ITA BASIC REASEARCH.
Enzyme inhibitors as therapeutic tools (with 2 case study)Tosim Mulani
Enzyme
Enzyme Inhibitor
Distribution of marketed drugs by biochemical target class.
Importance of Enzyme inhibition
Types of Enzyme inhibition
Some examples of Enzyme Inhibitors used as Therapeutic tool
Case Study – 1 Lovastatin Induced Control of Blast Cell Growth in an Elderly Patient with Acute Myeloblastic Leukemia
Case Study – 2 Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias
Enzymes
Enzymes are the substance that increases the rate of a reaction.
Reactants binds to the enzyme and products are released.
Enzymes can accelerate reactions as much as 10^16 overall of uncatalyzed reaction.
Specificity of an enzyme towards its substrate is control by its structure.
This unique fit of substrate with enzyme controls the selectivity of substrate for its product formation.
ENZYME INHIBITORS
Enzyme inhibitors are molecules that reduce the catalytic activity of enzymes.
The chemical substance which can react in place of substrate with the enzyme but is not transferred into products and block the active site of the enzyme temporarily or permanently is called enzyme inhibitor.
Reducing of effective enzymatic activity or complete blocking of enzyme may cause either complete death of cell or modifications in the pathways.
Distribution of marketed drugs by biochemical target class.
Importance of enzyme inhibition
For understanding the regulation of enzyme activity within the living cells.
Useful in elucidating the cellular metabolic pathways by causing accumulation of intermediates.
Identification of catalytic/functional groups at the active site of enzyme.
Provide information about substrate specificity of the enzyme.
Useful to study the mechanism of catalytic activity.
Enzyme inhibitors have therapeutic applications. Drugs are competitive or suicide in inhibitors.
Types of enzyme inhibition
Reversible inhibition
Competitive inhibition
Non – competitive inhibition
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
This power-point presentation will give a complete overview about enzymes, nomenclature of enzymes. Enzymes inhibition is also covered in this ppt. Along with some basin introduction to G- protein coupled receptors is also provided.
MUTUAL PRODRUG IS DISCUSSED HERE IN DETAIL WITH ITS MULTIPLE TYPES AND FUCTIONAL GROUPS IT IS USE FOR AND FAILURE WITH PRODRUGS, WITH PHARMACEUTICAL EXAMPLES AND STRUCTURE ARE ALSO SHARE, SYNTHETIC APLLICATIONS.
HERE PRESENTS AN OLIGONUCLEOTIDE THERAPY, ITS INTRODUCTION TO OLIGONUCLEOTIDE, ITS TECHNIQUES, DEVELOPED METHODS AND THEIR APP,LICATIONS IN PHARMACEUTICAL ARE HERE DISCUSSED IN DETAIL
OXIDATION [PHARMACEUTICAL PROCESS CHEMISTRY]Shikha Popali
INTRODUCTION TO OXIDATION , WHICH IS PROCESS OF ADDITION OF OXYGEN TO THE COMPOUND IN RPOCESS CHEMISTRY AND LIQUID PHASE OXIDATION AND OTHER OXIDISING AGENTS ARE DISCUSSED.
Synthetic reagent and applications OF ALUMINIUM ISOPROPOXIDEShikha Popali
SYNTHETIC REAGENTS AND APPLICATIONS OF ALUMINIUM ISOPROPOXIDE ITS ALTERNATIVE NAMES AND ITS PHYSICAL PROPERTIRS , HANDLING, STORAGE, PRECAUTIONS, PREPARATIONS, SYNTHETIC APPLICATIONS
PTC IS THE PHASE TRANSFER CATALYSIS HERE TYPES OF PTC ARE DISCUSSED , THEORIES OF CATALYSIS AND MECHANISM OF PTC, ADVANTAGES OF PTC, APPLICATION OF PTC
SWERTIA CHIRATA NATURAL PRODUCT OF PHARMACEUTICALSShikha Popali
HERE THE NATURAL PRODUCT SERTIA CHIRATA IS DISCUSSED WITH ITS COMMON NAME, CHEMICAL CONSTITUENTS, ACTIVE CONSTITUENTS, SAR, MEDICINAL ACTIVITY AND MORE
THE DCC I.E. DICYCLOCARBODIIMDE IS A REAGENT AND HERE THE DETAIL ACCOUNT ON IT IS GIVEN INCLUDING MOLECULAR WEIGHT, STRUCTURE, SYNTHESIS AND PHYSICAL PARAMETERS AND APPLICATIONS FOR OTERS SYNTHESIS ARE ALSO DISCUSSED, THE DIFFERENT SYNTHESIS WITH DCC COMBINATION ARE ALSO MENTIONED
COMPARATIVE EVALUATION OF DIFFERENT PARACETAMOL BRANDSShikha Popali
THE PARACETAMOL TABLETS IS COMMONLY TAKEN AND PRESCRIBED FOR FEVER , SO HERE WE HAVE MADE PRACTICAL IS IT TRUE EVALUATION LABEL AND WHICH BRAND IS MORE SAFE.
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Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
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2. Content
• Enzyme
• Kinetics of Enzymes
• Enzyme inhibition
• Classification of Enzyme inhibitors
• Enzyme inhibitors in medicine
• Enzyme inhibitors in basic research
• Rational design of non-covalently binding enzyme
inhibitors
• Rational design of covalently binding enzyme
inhibitors
3.
4. Enzymes
Enzymes are soluble, colloidal, organic catalysts, formed by
living cells specific in action, protein in nature, inactive at zero
degree celcius and destroyed by moist heat at 100 degree
celcius.
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.
5. Each enzyme is assigned with
1. Recommended name
2. Systemic name
3. Classification number.
6.
7. How enzyme catalyse reaction?
Enzymes provide a reaction surface and a suitable environment.
Enzymes bring reactants together and position them correctly so
that they easily attain their transitionstate confi gurations.
Enzymes weaken bonds in the reactants.
Enzymes may participate in the reaction mechanism.
Enzymes form stronger interactions with the transition state than
with the substrate or the product.
8. Enzyme Kinetics
• Enzyme kinetics is the study of the chemical
reactions that are catalysed by enzymes.
• In enzyme kinetics, the reaction rate is
measured and the effects of varying the
conditions of the reaction is investigated.
9. Michaelis–Menten Equation
• It explain how an enzyme can cause kinetic rate
enhancement of a reaction and why the rate of a
reaction depends on the concentration of enzyme
present.
• where KM is called the Michaelis Constant.
10. • KM is the substrate concentration required to reach half-
maximal velocity (vmax/2).
• KM is a measure of a substrate’s affinity for the enzyme.
• Considering the total enzyme concentration the maximal
rate, that the enzyme can attain is Vmax.
• Vmax is equal to the product of the catalytic rate
constant (kcat) and the concentration of the enzyme.
15. Classification of enzyme inhibitors
• The inhibition of a suitably selected target enzyme leads
to build up in concentration of substrates and a
corrosponding 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.
16.
17. Reversible Inhibition
• Inhibitor binds to Enzyme reversibly through weak non-
covelent interactions.
• An Equilibrium is established between the free inhibitor
and EI Complex and is defined by an equilibrium constant
(Ki)
• Reversible Inhibitors depending on concentration of E, S
and I, show a definite degree of inhibition which is
reached fairly rapidly and remains constant when initial
velocity studies are carried out.
E I EI
18. The reversible inhibition is further sub-divided into:
I. Competitive inhibition
II. Non-competitive inhibition
I. Competitive inhibition : The inhibitor which closely resembles
the real substrate (S) is regarded as a substrate analogue.
• The inhibitor competes with substrate and binds at the active site
of the enzyme but does not undergo any catalysis.
• As long as the competitive inhibitor holds the active site, the
enzyme is not available for the substrate to bind. During the
reaction, ES and EI complexes are formed .
• The relative concentration of the substrate and inhibitor and their
respective affinity with the enzyme determines the degree of
competitive inhibition.
• The inhibition could be overcome by a high substrate
concentration. In competitive inhibition, the Km value increases
whereas Vmax remains unchanged .
20. Example for Competitive Inhibition
Competitive inhibition accounts for the antibacterial action of
sulfanilamide which is a structural analog of PABA
Sulfanilamide inhibits the bacterial enzyme dihydropteroate
synthetase which catalyzes the incorporation of PABA into 7,8-
dihydropteroic acid.
NH2
SO2NH2COOH
NH2
21. II.Non-competitive inhibition :
• The inhibitor binds at a site other than the active site on the
enzyme surface. This binding impairs the enzyme function. The
inhibitor has no structural resemblance with the substrate.
• However, there usually exists a strong affinity for the inhibitor to
bind at the second site. In fact, the inhibitor does not interfere with
the enzyme-substrate binding. But the catalysis is prevented,
possibly due to a distortion in the enzyme conformation.
• The inhibitor generally binds with the enzyme as well as the ES
complex.
• For non-competitive inhibition, the Km value is unchanged while
Vmax is lowered .
• Heavy metal ions (Ag+, Pb2+, Hg2+ etc.) can non-competitively
inhibit the enzymes by binding with cysteinyl sulfhydryl groups.
22.
23. Irreversible Inhibition
o Inhibitor binds at or near the active site of the enzyme
irreversibly, usually by covalent bonds, so it can’t dissociate
from the enzyme
o No equilibrium exits
o Effectiveness of I is expressed not by equilibrium constant but
by a velocity constant, which determines the fraction of the
enzyme inhibited in a given period of time by a certain
concentration of the I.
E I EI
24. Suicide inhibition:-
• Suicide inhibition is a specialized form of irreversible inhibition. In this
case, the original inhibitor (the structural analogue/competitive
inhibitor) is converted to a more potent form by the same enzyme
that ought to be inhibited.
• The so formed inhibitor binds irreversibly with the enzyme. This is in
contrast to the original inhibitor which binds reversibly.
• A good example of suicide inhibition is allopurinol an inhibitor of
xanthine oxidase, gets converted to alloxanthine, a more effective
inhibitor of this enzyme.
• The use of certain purine and pyrimidine analogues in cancer therapy
is also explained on the basis suicide inhibition. For instance, 5-
fluorouracil gets converted to fluorodeoxyuridylate which inhibits
the enzyme thymidylate synthase, and thus nucleotide synthesis
25. 3. Allosteric inhibition
The details of this type of inhibition are given under allosteric
regulation as a part of the regulation of enzyme activity in the living
system.
Enzyme inhibition by drugs
Enzymes are the natural targets for development of pharmacologic
agents. Many of the drugs used in the treatment of diseases act as
enzyme inhibitors.
l Cholesterol loweing statin drugs (lovastatin) inhibit the enzyme HMG
CoA reductase.
Drugs (tenofovir, emtricitabine) employed to
block HIV replication inhibit the enzyme viral reverse transcriptase.
Hypertension is often treated by the drugs (captopril, enalapril )which
inhibit angiotensin converting enzyme.
26. Enzyme inhibitors in medicine
• A selective inhibitor may block either a single enzyme or a
group of enzymes.
• This will results 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 derivative possessing appropriate
pharmacokinetic characteristics
27. • 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.
• Enzyme inhibitors used in treatment of bacterial,
fungal, viral and parasite diseases:
31. 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.
32. 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 in-vivo.
33. Rational design of non-covalently
binding enzyme inhibitors
• This class of inhibitors binds to the enzyme's active
site without forming a covalent bond.
• Therefore the affinity and specificity of the inhibitor
for the active site will depend on a combination of
the electrostatic and dispersive forces, and
hydrophobic and hydrogen-bonding interactions.
• To understand the design concepts of the various
types of non-covalently binding enzyme inhibitors, a
basic knowledge of the binding forces between an
enzyme's active site and its inhibitors is required.
34. Forces involved
in an inhibitor /
substrate
binding
Ionic
(electrostatic)
interactions
Hydrogen
bonding
Ion dipole and
dipole-dipole
interactions
Hydrophobic
interactions
Van der Waals
interactions
35. Rational design of covalently binding
enzyme inhibitors
• The targets for these inhibitors are the chemically
reactive groups found within the enzyme's active site.
These groups, in the majority of cases, are
nucleophiles.
• In some cases the -NH, and -COOH groups of the
enzyme's N- and C-termini, respectively, are also active
site nucleophiles, whereas enzymic cofactors may also
provide targets for covalently binding inhibitors.
• Arginine is the only common amino acid that has an
electrophilic side chain and it also can be modified with
suitable nucleophilic agents.
36. Targets for
covalently binding
enzyme inhibitors
Nucleophiles such as –OH
group of
serine,threonine, tyrosine
-SH group of cysteine
-COOH groups of aspartic
and glutamic acid residues
imidazole ring of histidine
£-amino group of lysine