In silico methodology

In silico property prediction is needed more than ever to cope with the screening overload. Improved prediction technologies are continuing to emerge [13,14]. However, reliably measured physicochemical properties to use as training sets for new target applications have not kept pace with the in silico methodologies. 

Fundamentally, REACH is spurring the international acceptance of new risk assessment procedures, such as the use of in-silico methodologies. From a risk management perspective, regulatory agreement at the EU level can also provide a strong political force for action at an international level. As the only internationally endorsed RRS guidance is based on the current EU document... 

Alternative tests can be divided into two categories in vitro and in silico. In vitro methods refer to the fact that experiments are done in a tube, generally. In silico methods refer to the use of the computer to model a certain property of interest. Below, we will analyze these two categories, and which criteria can be used to choose a suitable methodology. 

Recently, microconstant measurements have been validated for 25 drug molecules, based primarily on multiwavelength spectroscopy. The apphed methodologies, however, are difficult and limited up to triprotic molecules when no symmetry constraints are present.In more complex cases, the microspecies resolution is still possible by applying some in silico methods for predicting ionization constants. 

Bioinformatics is a new and exciting subject developing its own methodologies, approaches and nomenclature with an elan which has not suffered from lack of precision about defining exactly what the subject is. As might be expected of a product of the computer age, it depends heavily on internet and database access, which are the essential tools of what has become termed in silico research. A very readable introduction to the subject is provided by Attwood and Parry-Smith (1999). 

The toxicologist can still use of in silico technology36 to assess the chemical-based toxicity potential of various structural series and many molecular methodologies can still be applied, including covalent binding assays, mitochondrial assays and oxidative stress assays.29-37... 

While this approach still requires the melting temperature of the substance in question, that is, requires its existence, the full in silico calculation based on the structural formula is now possible. Several recent publications present computational programs for the prediction of solubility. These approaches are being used for the pre-screening of candidates in advance of their synthesis, or for the design of combinatorial libraries. In a review of the different methodologies and the quality of results obtained from the most useful procedures it is concluded that viable procedures now exist for the determination of solubility with less than 1 log unit uncertainty. This uncertainty is judged to be adequate for use in the above processes. In parallel with this, combination of a newly miniaturized shake flask experimental method and a computational approach for solubility prediction has been published. ... 

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