This document summarizes key concepts about allosteric drug effects. It defines important terminology like alpha, beta, and cooperativity. It explains that allosteric molecules can bind to sites on proteins and induce conformational changes that affect the protein's activity. This allows allosteric drugs to have unique effects compared to orthosteric drugs, including modulating but not fully activating or inhibiting receptor function. The document also describes how to detect and quantify allosteric effects using models to fit binding data.
Some of the enzyme possess additional sites, known as allosteric sites besides the active site . Such as know as allosteric enzyme. The allosteric sites are unique place on the enzyme molecules allosteric enzyme have one or more allosteric site.
HISTRY
The term allosteric has been introduced by the two Noble Laureates JACOB AND MONOD to denote an enzyme site different from the active site which non competitively bands molecule other than the substrate and may influence the enzyme activity.
Properties of allosteric enzyme
Effector may be positive or negative, this effector regulate the enzyme activity . The enzyme activity is increased when a positive allosteric effector binds at the allosteric site known as activator site. On the other hand negative allosteric effector bind at the allosteric site called inhibitor site and inhibit the enzyme activity
Some of the enzyme possess additional sites, known as allosteric sites besides the active site . Such as know as allosteric enzyme. The allosteric sites are unique place on the enzyme molecules allosteric enzyme have one or more allosteric site.
HISTRY
The term allosteric has been introduced by the two Noble Laureates JACOB AND MONOD to denote an enzyme site different from the active site which non competitively bands molecule other than the substrate and may influence the enzyme activity.
Properties of allosteric enzyme
Effector may be positive or negative, this effector regulate the enzyme activity . The enzyme activity is increased when a positive allosteric effector binds at the allosteric site known as activator site. On the other hand negative allosteric effector bind at the allosteric site called inhibitor site and inhibit the enzyme activity
Introduction
Examples of Protein-Ligand interactions
Protein-Ligand Interactions Can Be Described Quantitatively
Cooperative Ligand Binding Can Be Described Quantitatively by Hill Equation
Physical and chemical methods of protein-ligand interaction study
Verification of interactions
Public protein–protein interaction databases
Ligand docking
Conclusions
References
Protein ligand interaction by KK Sahu sirKAUSHAL SAHU
Introduction
Historical Aspects
What are proteins
- Structure
- Functions
What are ligands
- Binding Site
Protein ligand Interaction
In oxygen binding proteins(Reversible Binding) * Hemoglobin
* Structure of Hemoglobin
* Structure of myoglobin
* Quantitative description of Protein ligand interaction
* Ligand binding effected by protein structure
* Oxygenation and deoxygenation of hemoglobin
* Co-operative binding of oxygen
* Model for co-operative binding
* Hemoglobin also transports H+ and CO2
2. Complementary interaction :- The Immune system and immunoglobulins
*Introduction
*Structure of Antibodies
*Binding of Antigen to Antibody
Importance
Application
Conclusion
References
Proteins are dynamic molecules whose functions almost invariably depend on interactions with other molecules.
A molecule bound reversibly by a protein is called a ligand.
A ligand binds at a site on the protein called the binding site, which is complementary to the ligand in size, shape, charge, and hydrophobic or hydrophilic character.
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.
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 ADC product is composed of an anti-HER2 antibody conjugated via vc linker to Duostatin-3 (trastuzumab-vc-Duostatin-3). It has demonstrated a response in ovarian cancer treatment by a MOA (Mechanism of Action) of inhibiting cell division by blocking of tubulin polymerization.
Introduction
Examples of Protein-Ligand interactions
Protein-Ligand Interactions Can Be Described Quantitatively
Cooperative Ligand Binding Can Be Described Quantitatively by Hill Equation
Physical and chemical methods of protein-ligand interaction study
Verification of interactions
Public protein–protein interaction databases
Ligand docking
Conclusions
References
Protein ligand interaction by KK Sahu sirKAUSHAL SAHU
Introduction
Historical Aspects
What are proteins
- Structure
- Functions
What are ligands
- Binding Site
Protein ligand Interaction
In oxygen binding proteins(Reversible Binding) * Hemoglobin
* Structure of Hemoglobin
* Structure of myoglobin
* Quantitative description of Protein ligand interaction
* Ligand binding effected by protein structure
* Oxygenation and deoxygenation of hemoglobin
* Co-operative binding of oxygen
* Model for co-operative binding
* Hemoglobin also transports H+ and CO2
2. Complementary interaction :- The Immune system and immunoglobulins
*Introduction
*Structure of Antibodies
*Binding of Antigen to Antibody
Importance
Application
Conclusion
References
Proteins are dynamic molecules whose functions almost invariably depend on interactions with other molecules.
A molecule bound reversibly by a protein is called a ligand.
A ligand binds at a site on the protein called the binding site, which is complementary to the ligand in size, shape, charge, and hydrophobic or hydrophilic character.
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.
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 ADC product is composed of an anti-HER2 antibody conjugated via vc linker to Duostatin-3 (trastuzumab-vc-Duostatin-3). It has demonstrated a response in ovarian cancer treatment by a MOA (Mechanism of Action) of inhibiting cell division by blocking of tubulin polymerization.
• Enzyme catalysis is the process by which there is an increase in the rate of a reaction through a biological molecule called an enzyme.
• For a reaction to be successful, the molecules of the reactants should contain sufficient energy to cross the energy barrier, i.e., the activation energy.
Introduction-Some of the enzymes possess additional sites, known as allosteric sites (Greek; allo-other) besides the active site. Such enzymes are known as allosteric enzymes. The allosteric sites are unique places on the enzyme molecules; allosteric enzymes have one or more allosteric sites
1. Receptors
2. Receptor dynamics
3. Drug receptor binding
4. Agonists & Types of Agonists
5. Antagonists
6. Constants related to antagonists
7. Types of antagonists
8. Mechanisms of actions of receptors
9. Thank you
This presentation intends to offer the basic features of plant metabolism along with the different types of mechanisms to regulate and control the metabolic pathways.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
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Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
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2. Outline
• Introduction
• New Terminology
• Protein Allosterism
• Allosteric Phenotypes
• Unique Effects of Allosteric
• Modulators
• Detecting Allosterism
• Quantifying Allosteric Effect
3. Introduction
• Allosteric molecules can bind to virtually any site on the target protein and show it’s activity.
• If a molecule is bound to the protein at any site the conformational movement of that protein may be affected.
• These effects are allosteric and have become a very important part of new drug discovery.
4. New Terminology
• α = Quantifying the effect of an allosteric modulator on the affinity of a protein for another molecule.
• β = Quantifying the effect of an allosteric modulator on the efficacy of an agonist binding to a receptor protein.
• Cooperativity = The effective interaction between the two cobinding allosteric molecules on the protein.
• Ensemble = A collection of protein molecules will have a selection of different conformations of similar free energy.
• Allosteric Modulator = Helps the protein to bind the cell with the ligand by binding with the protein.
• Negative allosteric modulator = Reduces the affinity or the efficacy of an agonist for a receptor.
• Positive allosteric modulator = increases the affinity and/or the efficacy of an agonist for a receptor.
• Probe dependence = Variation of activity of an allosteric modulator as it modifies the protein interaction with various probes
5. Protein Allosterism
• Allosteric interactions on proteins such as receptors and ion channels occur through the binding of a molecule onto the protein to affect its free
energy of conformation.
• Thus there is a conformational change occurs.
• The energy of the protein depends on the binding but not on the size of the ligand.
• Binding of a ligand with an enzyme with conformational change of the enzyme is referred to as “induced fit” by Daniel Koshland.
• The binding of a ligand initiates a process of conformational selection within the ensemble.
The process of conformational
selection by allosteric ligands
6. Dose-response curve for the binding of a ligand to a single subunit protein and to a protein made up of three identical
cooperatively linked subunits (black curve labeled “trimeric cooperativity”). For the trimer the binding of the
ligand to one subunit promotes the binding to the second and the third, causing the binding curve to be steeper
than that for a monomer.
• The binding of a molecule to one subunit alters the subsequent binding
of molecules to other subunits.
7. COOPERATIVE BINDING OF OXYGEN TO HEMOGLOBIN
• Hemoglobin is a tetrameric protein that binds and transports four oxygen molecules per unit and then releases them to myoglobin.
• The binding of oxygen to hemoglobin is allosterically cooperative.
• Oxygen readily binds to hemoglobin at the high pO2 values in the lung.
• Tetrameric cooperativity of oxygen binding to hemoglobin optimizes the delivery of oxygen to tissues
8. The product of enzyme II (compound C; isoleucine) is structurally different from substrate A (threonine), yet inhibits enzyme I through an
allosteric site. Panel on right shows the inhibition of the utilization of threonine in threonine less mutants of Escherichia coli by isoleucine in the
presence of 10 mM (open circles) and 20 mM L-threonine. This system is optimal for control of output since the overall product then controls the
initial rate of the reaction cascade.
• Proteins such as enzymes can bind molecules at multiple sites to modify their activity.
Negative feedback inhibition by the product of an enzyme cascade
9. ALLOSTERIC PHENOTYPES
• In general there is no way to predict the effects of an allosteric ligand.
• Upon binding an allosteric ligand, a receptor may have altered affinity , efficacy
or be directly stimulated by the modulator to produce response.
Three characteristic parameters of allosteric ligands. Considering a receptor receiving physiological input, the allosteric ligand can alter the
affinity of the endogenous agonist through a cooperativity term α, modify the efficacy of the endogenous agonist through a cooperativity term β or
itself produce direct agonism through a positive allosteric efficacy denoted τB. There are no constraints on the direction or magnitude of any of
these effects for any given allosteric ligand-endogenous agonist pair.
10. The various possible effects of an allosteric modulator on the response to an agonist
13. • Allosteric antagonists have the capability of being probe dependent and thus show differential blockade of different probes of the CCR5
receptor.
• TAK779 shows preferential potency for the blockade of CCL3L1-induced receptor internalization over HIV-1 entry.
• TAK652 shows a more favorable profile of greater potency for HIV-1 entry over CCL3L1-induced internalization.
14. UNIQUE EFFECTS OF ALLOSTERIC MODULATORS
The result of an allosterically modulated system can be different for different agonists. This and the property of saturation of effect cause allosteric
modulators to have a unique range of activities. These are;
• The Potential to Alter the Interaction of Very Large Proteins
• The Potential to Modulate but not Completely Activate and/or Inhibit Receptor Function
• Preservation of Physiological Patterns
• Reduction in Side-Effects
• Can Produce Texture in Antagonism
• Can Have Separate Effects on Agonist Affinity and Efficacy
• Allosteric Modulators Exercise “Probe Dependence”
15. The Potential to Alter the Interaction of Very Large Proteins
Disruption of the interaction of two proteins with multiple points of interaction.
16.
17.
18. The Potential to Modulate but not Completely Activate and/or Inhibit Receptor Function
pIC50 curves for allosteric antagonists that produce limite
maximal blockade of functional effects.
20. Can Have Separate Effects on Agonist Affinity and Efficacy
Effects of allosteric modulators that have opposite effects on agonist affinity and efficacy
23. QUANTIFYING ALLOSTERIC EFFECT
Alteration of kinetics of receptor dissociation by a PAM and NAM
The following equation defines the response to an agonist (A) in the presence of an allosteric modulator (B)
24. Fitting data to the model of allosteric function; Agonist KA5300 nM, τ 53, Em5100
• Panel A: Antagonism fit to the model for a negative allosteric modulator of KB5100 nM, α50.3, β 50.2. Curves shown in the absence and
presence of 300 nM 2 μM and 10 μM negative modulator.
• Panel B: Data for a PAM of KB5100 nM, α520, β 52. Curves shown in the absence and presence of 3 nM 20 nM and 100 nM positive
modulator
25. Fitting data to the model of allosteric function for modulator with direct agonist action for probe agonist KA5100 nM, τ 53, Em5100
Fitting data to the model of allosteric function for modulator with direct agonist action for control probe agonist KA5100 nM, τ 53, Em5100
26. Thank You for Being Patience
Success is not that what we always see