Module 3R    Tox receptor Author: Angelo Vedani
3-D Tox receptor database in the internet A A A
Welcome !
Module 3R
Draize test replacement
Sensitization in-vitro?
Pain
Tox receptor
Tox receptor
Concept
Prediction
Mechanisms
Database
Surrogates
Active compounds
Toxic
Harmless
Use
5D-simulation
Metabolites
Docking
Affinity
Toxicity
Impact
Reduce + Refine?
Implementation of the 3Rs
Pyrogen test in vitro
Replacement
Receptor modeling
3R-Bologna declaration
Authors
Continuing Education
Contact
The aim of the foundation Biographic Laboratory 3R is the creation of a virtual laboratory in the internet, for the computer supported evaluation, of unwanted effects, which can be caused by drugs, chemicals and metabolites.
Inhaltsverzeichnis
Receptor based toxicity
Estimation of the unwanted effects of potential drugs, active substances/chemicals and their metabolites with the help of a Tox receptor database.
From the 3D structure of the test substance to the receptor model
From the entry of the chemical structure via internet to the judgement of the toxicity: 1. Calculation of receptor models from receptor modelling and 5D-QSAR simulation. 2. Calculation of the affinity between the three dimensional structure of substances and it’s possible metabolites and the receptor models.
The steps of an in silico analysis
1. Structure of the active substance 2. Structure of the metabolites 3. Docking onto the receptor surrogate 4. Definition of affinity 5. Toxic potential
Is a safe prediction possible?
A safe prediction of the toxic effects of a chemical or a drug is possible if the receptor binding as the rate determining step triggers the toxic effect.
Assembly of the database
The quality of the prediction and the whole concept also depends on the number of validated receptor models and of the number of reference substances.
Bioregulators
5 structure models (receptors, enzyme, DNA, ion channel), which mediate unwanted effects, are validated; others will follow.
Proof of biological activity
With virtual receptor surrogates, the biological activity of similar active compounds can be predicted.
Prediction of toxic effects
Virtual receptor surrogates can also predict the toxic activity of comparable substances. No false positive results occur!
The three dimensional structure alone is not enough
The harmlessness of substances can also be proven, even if the topographical form of the molecule fits into the binding pocket of the virtual receptor.
Use of the database
The database shall be made available free of charge to the chosen partners from universities, the pharmaceutical and chemical industries as well as to the accreditation authorities.
5D-simulation is necessary
The active substance and the receptor mutually adapt their shape, and lift the 3D up to a 5D simulation.
Metabolites
To postulate all of the possible metabolites of an active substance is relatively easy; to differentiate between active and inactive metabolites is more difficult.
Parallel evaluation
The form of an active agent with the best possible fit will be selected.
Affinity of substance A in comparison with substance B
Relative affinities are suitable enough because the receptor surrogate is created with known substances. Calibration curves exist that deliver absolute values.
Affinity correlates with toxicity
If the substance to be tested shows a high affinity to one of the surrogates in the 3D-Tox database, then there is a high probability that it would be risky to use this substance.
Cooperation increases the relevance!
A look into the future : open source concept and higher processor performance for everyone will make it possible, that the 3D-Tox receptor database will gain relevance for the 3R idea.
Is it possible to do with less animal testing?
Not everyone is of the same opinion. Chemicals and potential drugs must be judged in different ways.
The foundation Biographic–Laboratory 3R has made it a goal, to follow the underlying biochemical life processes on powerful computers. Although it will never be possible to simulate a cell or even an organism with a computer, databases such as the Tox receptor data base will be further augmented and used in the future, to help find solutions for ecological and ethical problems and conflicts (WebSite http://www.biograf.ch oder http://www.modeling.unibas.ch / E–Mail: admin@biograf.ch).