In Silico methods

In silico is an expression that means "performed using a computer simulation" and was coined in 1989 during the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico by a mathematician from National Autonomous University of Mexico (UNAM).

In silico models for predicting toxicological, biological and physico-chemical properties are models able to find relations between particular characteristics of molecules and the property of interest. Example of in silico methods are: (Q)SAR, Read-Across and Virtual Screening.

Quantitative Structure-Activity Relationship (QSAR) are computer-based models for the prediction of toxicological, biological and physico-chemical properties. QSAR models aim at establishing, if it exists, the relationship between structural-derived properties of chemicals and their properties, such as toxicity. For the relationship between the activity and the chemical information a mathematical function is used. The chemical information can be given by chemical descriptors or fragments. Many thousands of chemical descriptors have been proposed, constitutional, geometrical, physico-chemical, topological, etc.
In the specific case of the evaluation of a qualitative relationship, for instance between the presence of a certain chemical fragment and the occurrence of a certain toxicity effect, the typical name is structure-activity relationship (SAR). (Q)SAR is used sometimes to refer to both QSAR and SAR. Here we will present QSAR and SAR together, using the acronym QSAR.

Read-across is a very simplified version of QSAR model. Basically, the property of one or few chemicals is predicted on the basis of one or more similar compounds, using or not some chemical descriptors.

Virtual screening are docking simulation based methods used to evaluate the binding between a chemical compound and a biological macromolecule, such as a protein.

 

Download the Introductory leaflet on in-silico methods

Watch the ORCHESTRA video documentary based on interviews with regulators, industry and QSAR developers.

Click here to view an interview with Professor Wim de Coen, Head of Evaluation 1 at the European Chemicals Agency (ECHA)

 

Areas of applicability

QSAR models have been developed for many applications:

Typically, the performance of the QSAR models are better for physico-chemical properties, and decrease with the increase complexity of the studied system. For certain human endpoints, such as carcinogenicity and developmental toxicity, the general position is that in silico models should be used as unique tool, but as support for the evaluation based on several methods.

For aquatic toxicity, most of the models address acute toxicity, mainly in fish. Results are good for chemicals which do not carry residues which increase their toxicity, which applies to about 30% of the cases. Specific models for more toxic compounds should not be used in these cases.

Models for mutagenicity (mainly Ames test) generally give good results (accuracy about 80%, which is close to the test reproducibility).

Models for bioconcentration factors (BCF) give good results (R2 about 80%; error about 0.5 log unit). Care should be taken if the predicted value is close to the threshold, while if the predicted value is well above or below the BCF threshold, the prediction is much more reliable.

Models for carcinogenicity give a quite large error. About one out three chemicals is wrongly predicted. Better results can be obtained if the applicability domain of the model is evaluated. At least three models for carcinogenicity should be used, because the results vary. In case of agreement, the prediction is more reliable.

Relation/Comparison with other methods

Any model, such as animal models (also called in vivo) or cellular models (in vitro models), is a system which applies to a specific situation, and simplifies a complex system, which cannot be used experimentally for investigation. For instance, in case of toxicity studies, the target is human health, and for environmental studies the target may be a certain ecosystem. In practice, all current models simplify the final target. The rabbit model will never replace the human being, and similarly the trout used in a tank cannot replace the complex environmental system where many different fishes, and animal, and environmental conditions exist. Methods like in vitro and in silico models are often called alternative methods, because they can be used as alternative to animal models. In addition, these methods can be used to provide further information, to better address the final target: human beings and environment. Thus, it would be reductive to see in silico methods simply as surrogate of animal models.

The comparison and integration of in vivo, in vitro and in silico, have been discussed during the workshop organized by the EC funded project RAINBOW.

The debate

There is a debate on the use of QSAR in particular, and in silico models in general. The acceptability of these tools depends on the user and the purpose.  Within that debate, the major criticisms are that ‘In silico models are not reliable’, that ‘toxicity is too complex to be modelled’ and that ‘only the real experiment on the animal will provide the real result’.

All in silico models should give a proof of their performance. In the past, the classical models were developed using all data, which were used to build up a model without any validation of the model. The points were fitted in a linear regression, and no demonstration was given if this regression was applicable to other chemicals (Kaiser, K. L. E. at all, 1999).

The interest on the use of in silico models for regulatory purposes contributed to the discussion on the validation of the in silico models (for more info refer to the regulatory context area of this website). A clear definition of the possible use of the model should be given, and pitfalls clearly indicated, for all in silico methods, such as QSAR, read-across and docking studies. Examples in this direction are the tools developed within CAESAR, which guide the user, indicating results on similar compounds, and errors.

Even if toxicity is complex, some phenomena are simplier and rules have been identified. For instance, in case of aquatic toxicity most of the chemicals can be explained with quite simple relationships (for more info refer to the DEMETRA project). Genotoxicity has been modeled in large extent on the basis of some toxic fragments or related QSAR models (more info at CAESAR project). Improvement seems possible, on the basis of more data (and there are huge initiatives in this direction, such as ToxCast), better models, and integration of models.

Even in vivo models cannot provide all answers. A wise integration of models, including in silico models, can only improve our knowledge. In silico models take advantage of computers to better examine the data and information available. Disregard this would mean not to use all pieces of information we have.

Watch the ORCHESTRA video documentary based on interviews with regulators, industry and QSAR developers.

Click here to view an interview with Professor Wim de Coen, Head of Evaluation 1 at the European Chemicals Agency (ECHA)

Challenges

In silico tools can offer immediate, world-wide, free (in many cases) access to a formidable amount of tools: databases, libraries of structures and properties, literature studies, models. Within a few years ToxCast will produce experimental data on 100,000 chemicals, omics will produce huge amount of data, HTPS will generate unprecedented amount of data. No single human expert will have the time and the possibility to dig these incredibly large collections of results. Even today thousands of chemicals are present in libraries with their toxicity properties.

The sooner the correct use of in silico models will be widespread, the better, in order to take advantage and exploit these results.

QSARs in REACH? - Uses, issues and priorities

The documentary 'QSARs in REACH?' is based on interviews with regulators, industry and QSAR developers, and addresses some of the key issues and priorities in the further use of QSARs within REACH. 

The documentary was first shown at the ORCHESTRA booth at the 2011 SETAC Europe conference in Milan.   Here it can be viewed online in 4 short separate sections.  (See technical advice on viewing below.)  The list of 20 contributors who are interviewed, and our thanks to them and others, are in the final video section.

 


Introduction (1 min)  &  Regulatory perspectives  (8 mins)

 

Interviews with regulators, including ECHA and national regulators on how they see the role and potential of QSAR models within REACH. 

 

 


What makes a good QSAR model?  (9 mins)

Interviews with QSAR developers on the value and limits of QSAR models, to offer an understanding of the core issues of what makes a good QSAR model, the importance of using models appropriately, and how to review or question the outputs.   

 


Industry perspectives.  (8 mins)

 

Interviews with industry representatives on the ways in which they are currently using QSAR models, and their current concerns and priorities for enabling wider use within REACH. 

 


Future directions  (4 mins)  &  List of contributors

 

Comments from all stakeholders on future directions.


 

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Documents and Faqs

This page lists various documents published by Orchestra.

In silico methods leaflet

The leaflet is intended as a concise and accessible explanation of in silico methods, and the issues around them, for people who want to know about them, and/or what to understand what the ORCHESTRA project is about.

The leaflet is available in English, French, German and Italian languages.

Orchestra newsletter issue 1 June 2010

Newletter issues

Issue 1, June 2010 : "New Website
Dissemination Strategies
and Workshop"

Check also the FAQ , Glossary and Bibliography sections in this site.