In silico profiling

Novartis uses the In Silico Profiling web tool. Available properties include the octanol water partition coefficient log P, molar refractivity, flexibility index, hydrogen bonding characteristics and molecular polar surface area. Various drug properties, such as intestinal absorption, BBB permeability or Plasma Protein Binding (PPB) are calculated based on in-house models. 

A large database of pharmacophores was developed by Inte Ligand [40]. These models were automatically derived from available protein structures with the software LigandScout [41] or were built manually for selected targets, for which no structural information is available. This pharmacophore database is suitable for in silico profiling of compounds yielding early on potential liabilities of molecules, which have to be proven experimentally. 

Gruchattka E, Hadicke O, Klamt S, Schutz V, Kay-ser O (2013) In silico profiling of Escherichia coli... 

In particular, in silico methods are expected to speed up the drug discovery process, to provide a quicker and cheaper alternative to in vitro tests, and to reduce the number of compounds with unfavorable pharmacological properties at an early stage of drug development. Bad ADMET profiles are a reason for attrition of new drug candidates during the development process [9, 10]. The major reasons for attrition of new drugs are ... 

As discussed above, all ADMET aspects are dependent on each other and should all be considered when making predictions. Integrated analysis of different aspects of drug pharmacokinetic profiles is yet another future trend. Ultimately, drug ADMET properties should be predicted based on an integration of a compilation of in silico models reflecting different aspects of the process. 

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. 

During the early stages of drug discovery, a suitable candidate must be selected from a limited number of structurally related compounds that may have a similar pharmacological profile. At that point, information from in vitro systems would provide important and particularly useful selection criteria. However, results from in vitro models are often not yet available at the early phases of development, or they exist only for a limited number of compounds. Accordingly, there is an urgent need for in silico methods that would allow prediction of the pharmacological properties in humans from the experimental model systems. 

In silico ADME profiling of compound libraries in early discovery has become a valuable addition to the research toolbox of computational and medicinal chemists. A computational alert was developed by Lipinski based on the physico-chemical... 

Schuster, D., Laggner, C., Steindl, T.M. and Langer, T. (2006) Development and validation of an in silico P450 profiler based on pharmacophore models. Current Drug Discovery Technologies, 3, 1—48. 

As illustrated in the next section, the use of biological fingerprints, such as from a BioPrint profile, provides a way to characterize, differentiate and cluster compounds that is more relevant in terms ofthe biological activity of the compounds. The data also show that different in silico descriptors based on the chemical structure can produce quite different results. Thus, the selection of the in silico descriptor to be used, which can range from structural fragments (e.g. MACCS keys), through structural motifs (Daylight keys) to pharmacophore/shape keys (based on both the 2D structure via connectivity and from actual 3D conformations), is very important and some form of validation for the problem at hand should be performed. 

In this section, discussion of physicochemical profiling is limited to solubility, permeability, drug stability, and limited solid-state characterization (as we will see in Section 3.4, there are other physical-mechanical properties that must also be considered). For convenience, methods available for physicochemical profiling are discussed under the following categories computational tools (sometimes referred to as in silico tools), HTS methods, and in-depth physicochemical profiling.16... 

Horvath, D. and Jeandenans, C. Neighborhood behavior of in silico structural spaces with respect to in vitro activity spaces - a novel understanding of the molecular similarity principle in the context of multiple receptor binding profiles./. Chem. Inf. Comput. Sci. 2003, 43, 680-690. 

Fig. 14.9 Individual components of multidimensional optimization. This approach requires experimental compound profiling against key properties, which should be done on a designed compound subset to maximize information with a minimum number of molecules. These data are used to derive models for key properties, which are applied during the next design cycle. The results then led to augmented models. The process is characterized by a tight integration of in vitro and in silico tools for profiling compound series to guide chemical optimization.

Kiister H etal.. Development of bioinfo rmatic tools to support EST-sequencing, in silico- and microarray-based transcriptome profiling in mycorrhizal symbioses, Phytochemistry 68 19—32, 2007. 

Ekins, S., Mestres, J., Testa, B. In silico pharmacology for drug discovery methods for virtual ligand screening and profiling. Br. J. Pharmacol. 2007, 152, 9-20. 

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