Design of enzyme inhibitors as drugs
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The document discusses the design of enzyme inhibitors as drugs. It describes different types of enzyme inhibitors including reversible and irreversible inhibitors. There are four approaches to designing competitive reversible inhibitors: simple competitive inhibition, alternative substrate inhibition, transition state analog inhibition, and slow tight-binding inhibition. It also discusses the design of specific inhibitor types such as simple competitive inhibitors, alternative substrate inhibitors, and transition state analogs. Mechanism-based enzyme inactivators are also covered, providing vigabatrin as an example drug that inactivates enzymes through conjugate addition.
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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.
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They have a molecular weight of less than 2000 Dalton.
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Handout:
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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
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B) Enzyme kinetics
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D) Adverse drug reactions due to enzyme inhibition
8) Enzyme activation by drugs
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B) JAK-STAT pathway
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D) Toll like Receptors
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13) Conclusion
14) References
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1. There are several types of drug receptors that mediate the effects of drugs, including ion channel-linked receptors, G-protein-linked receptors, enzyme-linked receptors, and intracellular receptors.
2. Drugs interact with specific receptors through precise physiochemical and spatial interactions, and this binding can lead to responses by activating ion channels, enzymes, or other intracellular signaling pathways.
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1) The document discusses several different types of drug targets including enzymes like monoamine oxidase, cyclooxygenase, HMG-CoA reductase, dihydrofolate reductase, kinases, hydrolases, phosphodiesterases, carbonic anhydrase, and histidine decarboxylase.
2) It provides examples of drugs that target these enzymes, such as monoamine oxidase inhibitors, COX-2 inhibitors like celecoxib, statins, methotrexate, kinase inhibitors gefitinib, ACE inhibitors like captopril, PDE5 inhibitors like sildenafil, and carbonic anhydrase inhibitors acetazolamide.
3
rational enzyme design
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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.
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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.
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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
Artificial enzymes
This document summarizes information about synzymes, which are artificial enzymes designed to mimic natural enzymes. It discusses the ideal characteristics of synzymes, such as having a hydrophobic binding site and catalytic group similar to enzymes. Approaches for designing synzymes include using cyclodextrins or cyclophanes to position catalytic groups to mimic enzyme active sites. Examples of reactions catalyzed by synzyme designs include palladium-based reactions and multi-step reactions through immobilizing multiple catalysts on polymers.
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Stability against proteolysis (duration of activity)
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Artificial enzymes presentation.pptx
An artificial enzyme is a synthetic organic molecule or ion that mimics one or more functions of an enzyme.
Molecules are designed and modified to achieve some desirable features of enzymes.
Protein engineering has been developed to design and synthesize molecules with the attributes of enzymes for non-natural reactions.
They have a molecular weight of less than 2000 Dalton.
They have the ability to stabilize at a higher temperature.
They are also known as synzymes or enzyme mimics.
Targets of drug action: Enzymes
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
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This document discusses enzyme inhibition as it relates to drug discovery. It begins by providing background on the target-based approach to drug discovery, noting that enzymes are excellent drug targets. It then discusses different drug discovery approaches and the multi-stage drug discovery process. Several sections provide examples of enzyme inhibitors that are used as drugs to treat various diseases and medical conditions. The mechanisms of reversible and irreversible enzyme inhibition are also summarized. Finally, specific classes of enzyme inhibitors are discussed in more detail, such as kinase inhibitors, ACE inhibitors to treat hypertension, and statin drugs to lower cholesterol.
Drug receptor-interactions
1. There are several types of drug receptors that mediate the effects of drugs, including ion channel-linked receptors, G-protein-linked receptors, enzyme-linked receptors, and intracellular receptors.
2. Drugs interact with specific receptors through precise physiochemical and spatial interactions, and this binding can lead to responses by activating ion channels, enzymes, or other intracellular signaling pathways.
3. The interaction between a drug and its receptor is described using principles from enzyme kinetics, with terms like efficacy, potency, affinity, agonists, partial agonists, and antagonists. Competitive and non-competitive antagonism can alter the response to receptor activation.
ENZYME INHIBITION MORE INTERESTING IN CHEMISTRY WAY
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.
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1) The document discusses several different types of drug targets including enzymes like monoamine oxidase, cyclooxygenase, HMG-CoA reductase, dihydrofolate reductase, kinases, hydrolases, phosphodiesterases, carbonic anhydrase, and histidine decarboxylase.
2) It provides examples of drugs that target these enzymes, such as monoamine oxidase inhibitors, COX-2 inhibitors like celecoxib, statins, methotrexate, kinase inhibitors gefitinib, ACE inhibitors like captopril, PDE5 inhibitors like sildenafil, and carbonic anhydrase inhibitors acetazolamide.
3
rational enzyme design
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Enzyme Inhibition
This document discusses different types of enzyme inhibition including reversible and irreversible inhibition. Reversible inhibition includes competitive, uncompetitive, non-competitive, mixed, partial, substrate and allosteric inhibition. Competitive inhibitors compete with the substrate for the active site, while uncompetitive inhibitors bind only to the enzyme-substrate complex. Non-competitive inhibitors bind at a site other than the active site. Irreversible inhibitors form covalent or non-covalent bonds that permanently inactivate the enzyme. Understanding inhibition is important as many drugs and toxins function through inhibiting enzymes.
Actvation energy and enzymes
Enzymes regulate chemical pathways in cells and lower the activation energy of reactions, increasing reaction rates. Enzymes have an active site that binds to substrates, catalyzing the reaction to form products. Factors like pH, temperature, and inhibitors can impact an enzyme's activity by changing its shape. Feedback inhibition regulates metabolic pathways by inhibiting enzymes when product concentrations are high.
Enzyme inhibitors
ENZYME INHIBITORS, CLASSIFICATION, MECHANISM OF ENZYME INHIBITION, ENZYME INHIBITION IN MEDICINE AND RESEARCH
Enzyme inhibition
Inhibitors are chemicals that reduce the rate of the enzymatic reactions,
They are usually specific and work at low concentrations,
They block the enzyme, but they do not usually destroy it,
Many drugs and poisons are inhibitors of enzymes in the nervous system,
Inhibitors of the catalytic activities of enzymes provide both pharmacologic agents and research tools for the study of the mechanism of enzyme action.
Enzyme inhibitors, reversible_and_irreversible
Reversible and irreversible enzyme inhibitors can be classified based on their binding interactions with enzymes. Reversible inhibitors form non-covalent complexes with enzymes and their activity can be restored upon removal of the inhibitor. Irreversible inhibitors form covalent bonds and permanently inactivate the enzyme. Reversible inhibitors include competitive inhibitors, which bind the active site, non-competitive inhibitors, which bind elsewhere and alter the enzyme's shape, and uncompetitive inhibitors, which only bind the enzyme-substrate complex. Irreversible inhibitors are either active site directed, covalently binding the active site, or suicide inhibitors, which are transformed by the enzyme into a reactive molecule that inactivates it. The Michaelis-Menten equation
Rational design of non- covalently and covalently binding.pptx
Rational design of covalently binding enzyme inhibitors
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Forces Involved in Forming the Enzyme Inhibitor Complex
STEREOCHEMISTRY AND DRUG ACTION.pptx
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
Artificial enzymes
This document summarizes information about synzymes, which are artificial enzymes designed to mimic natural enzymes. It discusses the ideal characteristics of synzymes, such as having a hydrophobic binding site and catalytic group similar to enzymes. Approaches for designing synzymes include using cyclodextrins or cyclophanes to position catalytic groups to mimic enzyme active sites. Examples of reactions catalyzed by synzyme designs include palladium-based reactions and multi-step reactions through immobilizing multiple catalysts on polymers.
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ENZYME INHIBITION MORE INTERESTING IN CHEMISTRY WAY
ENZYME INHIBITION MORE INTERESTING IN CHEMISTRY WAY
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by Dr. N. Sivaranjani, MD
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Enzymes catalyze chemical reactions in living cells. Understanding how enzymes work allows rational drug design of enzyme inhibitors. Enzymes lower the transition state energy of reactions, accelerating rates. Studying enzyme kinetics using Michaelis-Menten equations reveals how substrates and inhibitors interact with enzymes. Different inhibitor types - competitive, non-competitive, uncompetitive - bind enzymes in distinct ways to slow reactions. Transition state analogs that mimic enzyme-substrate interactions make potent inhibitors.
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Design of enzyme inhibitors as drugs
- 1. DESIGN OF ENZYME INHIBITORS AS DRUGS By : Ms. Tabhitha K Guide : Mr. Sampath Ayyappa G, M.Pharm
- 5. DESIGN OF SIMPLE COMPETITIVE INHIBITORS
- 11. DESIGN OF ALTERNATIVE SUBSTRATE INHIBITORS
- 13. DESIGN OF TRANSITION STATE ANALOGS
- 14. DESIGN OF MULTISUBSTRATE ANALOGS
- 20. THANK YOU