Module 3R    Receptor modeling Author: Angelo Vedani
Receptor modeling: a virtual approximation of reality A A A
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Module 3R
Draize test replacement
Sensitization in-vitro?
Pain
Tox receptor
Implementation of the 3Rs
Pyrogen test in vitro
Replacement
Receptor modeling
Lock and key
Fexible entities
Receptor structure
Endogenous ligands
Modeling
3D world
Parking
Binding strength
Receptor model
Degree of abstraction
Evolution
Neurokinin
Prediction
Dioxin
Training
Reduce
3R-Bologna declaration
Authors
Continuing Education
Contact
How can the interaction between active ingredients (pharmaceutical or toxic) and receptors be mathematically determined? What is a virtual receptor? Molecular modeling? Never heard of it? And how can animals be saved in this way? In this module everything will be explained.
Inhaltsverzeichnis
Lock-and-key principle (1890)
«To use a visual example, I wish to say that, enzyme and glycoside must fit together like a lock and a key, to enable them to exert a chemical effect on each other.»
Felxible entities
The lock-and-key principle is a simplified model for the description of the interaction between an active ingredient and a receptor.
Three dimensional receptor structure
To determine the three dimensional structure of a receptor is a very time consuming peace of work. It is achieved with the use of x-ray diffraction by protein crystals.
Natural (endogenous) ligands
It is initially very helpful to know, how the natural substrate (ligand) binds to the receptor.
Fitting a putative ligand into the receptor binding pocket
The modeling of a hypothetical active substance takes place until the docking to the receptor becomes possible. At the same time the binding strength can be determined.
Docking with a computer
Efficient docking with a computer can only be carried out in 3D.
Docking is complex and time-consuming
The visual adaption of a potential active ingredient to a virtual receptor: a time-consuming calculation process.
Binding strength
From the interaction of the active substance with the receptor, the binding strength can be estimated, which is only possible with the aid of complex mathematics.
The building of a receptor model
There is no 3D structural model of more than 90% of all receptors.
Degree of abstraction of receptor models
Receptor models can show very different degrees of abstraction (in comparison to real biological receptors).
Simulated evolution of receptor models
The use of genetic algorithms for the optimization of receptor models has proven to have many advantages in comparison to “intuitively” deduced surrogates.
Example: The neurokinin-1 receptor
An example from pharmacology: the neurocinin-1 receptor. With the help of the well known endogenous subtrate (substance P) the model of the receptor can be described.
Prediction of activity
With such computer aided procedures, it is possible to drastically reduce the number of substances which are applied to animals. It is no longer necessary to test ineffective substances or substances with many side effects.
Substrates for the Ah-(dioxin) receptor
It has for the first time been possible to show with the Ah (Dioxin) receptor, that in silico procedures also can predict the acute toxicity of chemicals.
Training of a receptor model
No false positive or false negative predictions among 30 compounds. This level of precision has never in the past been achieved by any cellular in vitro procedure!
A contribution to the reduction animal testing
With the use of molecular modeling, fewer animal tests are necessary to successfully bring a new product onto the market, as it increases the chance, to recognise ineffective candidates before synthesis — particularly before they are tested in vivo.
With molecular modeling (also known as Computer Assisted Drug Discovery, CADD) pharmacological activity (binding strength to the target receptor) as well as unwanted side effects (binding to other receptors) can be calculated in silico (i.e – on the computer). The main advantage of CADD in comparison to all other procedures, is that it is not necessary to manufacture yet another potentially active substance only to test it.
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