In silico prediction methods

Herein we describe the application of in silico predictive methods and parallel chemistry to advance structure activity relationships (SAR) for series of molecules identified as inducers of the... 

Methods to predict the route and extent of metabolism include in vitro and in silico techniques. In vitro assays to determine metabolic stability or drug-drug interactions are typically carried out using hepatocytes or microsomes details of these in vitro assay procedures are described by Li (2001). However, in silico prediction and optimization methods are more useful when dealing with large datasets. 

The need to store the wealth of data produced by large scale biological projects and to provide a robust framework for analyzing and studying PPIs is obvious. Nearly all the projects described in Chapters 2 and 3, whether produced by experimental methods, in silico predictive techniques or extracted from the scientific literature, have their data collapsed and structured in databases (see Table 1). 

The relationship between chemical structure and activity has been recognized from early on, as the examples in Sec. 10.3.2 illustrate. Tbday, computerized expert systems allow the virtual screening of millions of possible structures with the objective to find the best candidates for development. However, the accuracy of such in-silico predictions is still low and it will take time before they can replace experimental discovery methods. 

In silico methods that are able to predict quantitative aspects of the interaction of a substrate with P-gp would be of great value. So far, modeling was applied mainly to lock-key-type reactions taking place in aqueous solution. The structural diversity and lipid solubility of P-gp substrates and the fact that their encounter with the transporter takes place in the lipid membrane and not in aqueous solution are new challenges for in silico predictions. Since all in silico models are based on experimental data, we first provide a short introduction to various P-gp assays and discuss their underlying principles (18.2). Secondly, we summarize the different in silico approaches (18.3), and, lastly, we discuss the parameters that are most relevant for the different in silico models (18.4). 

The flux balance approach is an elegant technique for analyzing biological pathways in that the approach allows metabolic networks to be quantitatively and qualitatively studied without knowledge of specific enzyme kinetic parameters. A combination of FBA and bioinformatics provides a rapid, economical, and predictive in silico screening method for potential strategies to produce a desired compound. 

E. coli metabohsm. The effects of gene deletions in the central metabolic pathways on the ability of the in silico metabolic networks to support growth were assessed and the in silico predictions were compared with experimental observations. It was shown that, based on stoichiometric and capacity constraints, the in silico analysis was able to qualitatively predict the growth potential of mutant strains in 86% of the cases examined. The synthesis of in silico metabolic genotypes based on genomic, biochemical and strain-specific information is possible, and systems analysis methods are available to analyze and interpret the metabolic phenotype. ... 

Livingstone DJ, Waterbeemd VD, Han 1 (2009) In silico prediction of human oral bioavailability. Method Prin Med Chem 40 433 51... 

In silico prediction of the in vivo dissolution behavior of amorphous systems is currently almost impossible. Thus, in vitro screening for the identification of suitable drug-excipient combinations with appropriate dissolution and/or high supersaturation potential has become a vital step in the development of ASDs. Today, supersaturation screening is commonly carried out by solvent-shift approaches (e.g., the co-solvent quench method) or by dissolution testing (e.g., amorphous film dissolution in solvent-casting approaches). These topics are discussed further in Sect. 5.3. 

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