In silico evaluation

For the in silico evaluation of carcinogenic potential of PFCs, 16 compounds were selected (see Table 2). 

A list of privileged scaffolds - several of which are natural-product derived - for target-family-biased combinatorial libraries was recently presented by Muller [94], These scaffolds were proven to produce biologically active compounds for more than one member of a given target family. A rough-and-ready in-silico evaluation... 

P. Braiuca, C. Ebert, L. Fischer, L. Gar-dossi, P. Linda, A homology model of penicillin acylase from Alcaligenes fae-calis and in silico evaluation of its selectivity, ChemBioChem 2003, 4, 615-622. 

Gombar VK, Silver IS, Zhao Z. Role of ADME characteristics in drug discovery and their in silico evaluation in silico screening of chemicals for their metabolic stability. Curr Top Med Chem 2003 3(11) 1205-1225. 

Ardao, I. and Zeng, A.-P. (2013) In silico evaluation of a complex multi-enzymatic system using one-pot and modular approaches application to the high-yield production of hydrogen from a synthetic metabolic pathway. Ghent. Eng. Sci, 87, 183-193. 

Vilar, S. Santana, L. Uriarte, E. Probabilistic neural network model for the in silico evaluation of anti-HIV activity and mechanism of action. J. Med. Chem. 2006, 49,1118-1124. 

FIGURE 3.38 The in-cerebro scheme for in-silico evaluation of the environmental or toxicological activities for a given target chemical (under concern or newly designed or synthesized), following and explicating the Toolbox QSAR computational facility, after (OECD-QSAR, 2013 Putz et al., 2012). 

The term virtual screening or in silico screening" is defined as the selection of compounds by evaluating their desirability in a computational model. The desirability comprises high potency, selectivity, appropriate pharmacokinetic properties, and favorable toxicology. 

If structural information of the protein target is available, e.g., a crystal structure, in silico screening of huge virtual compound libraries can be conducted by the use of docking simulations. Based on identified primary hits, structural variations of the ligand can be evaluated by computational modeling of the ligand-protein complex. 

A further insight is that the best workflow depends on a combination of factors that can in many cases be expressed in closed mathematical form, allowing very rapid graphical feedback to users of what then becomes a visualization rather than a stochastic simulation tool. This particular approach is effective for simple binary comparisons of methods (e.g., use of in vitro alone vs. in silico as prefilter to in vitro). It can also be extended to evaluation of conditional sequencing for groups of compounds, using an extension of the sentinel approach [24]. 

To date, many of the reported ADME/Tox models have been rule based. For example, some research groups have used relatively simple filters like the rule of 5 [93] and others [94] to limit the types of molecules evaluated with in silico methods and to focus libraries for HTS. However, being designed as rapid computational alert tools aimed at a single property of interest, they cannot offer a comprehensive picture when it comes to understanding ADME properties. 

The abundance of crystallographic information on the 3D structure of protein kinases, including knowledge of receptor-ligand complexes, has seen protein kinases feature consistently in datasets employed to both develop and evaluate methods for receptor-based screening. Indeed, the vast majority of literature surrounding protein kinases and receptor-based in silico... 

The information about internal and external validation for the model is used to evaluate the performance of the in silico tool. 

Finally, a QSAR evaluation of different chemicals from waste-related products and recycling is shown in order to underline how in silico models can be used as a valid tool to fill in the gaps and to obtain information on toxicological profile and physicochemical information on compounds. In particular, a focus on compounds suggested by EU project Riskcycle is presented. 

Qualitative Evaluation of Carcinogenic Potential of Some PFCs Using In Silico... 

In this chapter we will introduce and discuss the use of alternative methods to evaluate the carcinogenic potential of some PFCs. In detail, in silico (QSAR) models and BALB/c 3T3 CTA will be used to investigate the issue. 

Fig. 5.2. Two-step process for evaluation of intestinal drug absorption. The first step represents the prediction of intestinal permeability (e.g., over Caco-2 monolayers) from in-silico models or from physico-chemical...

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

Thomas, K. et al., In silico methods for evaluating human allergenicity to novel proteins International Bioinformatics Workshop Meeting Report, 23-24 February 2005, Toxicol. Sci., 88, 307, 2005. 

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