In silico method

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 ... 

Moreover, there is a clear and obvious need for experimental work to be conducted in support of the development of accurate in silico methods. Bioinformaticians, like all other scientists physical or biological or social, need... 

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 concept of the A shift in HTS solubility measurements is quite exciting. It means that DMSO can be used in solubility measurements and the measured values later corrected to DMSO-free conditions. So we can have speed and accuracy at the same time The pharmaceutical industry needs speed and accuracy, and will need these more in the future. In silico methods are no better than the data used to train them. 

Analytical methods for the determination of environmental concentrations (MEC) Models for predicting environmental Concentrations (PEC) In vivo/In vitro assays QSAR models In silico methods... 

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. 

Here we will address in particular QSAR, being more used. However, the idea is to extract the common criteria for all in silico methods. 

The fact that the model works, that is predictive, should be quite obvious. It is our opinion that this criterion should be applied to all in silico methods, not only QSAR, and actually to all alternative methods. The same applies to all criteria listed by REACH. 

The definition of the endpoint is essential to understand what kind of experimental systems is being modeled by the in silico method. 

From the preliminary list of 16 compounds of concern, 14 compounds have been selected for the application of in silico methods because metals, and generally inorganic compounds, cannot be subjected to QSARs analysis. 

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. 

Application of ultra-high-throughput in silico estimation of biopharmaceutical properties to the generation of rule-based computational alerts has the potential to improve compound selection to those drug candidates that are likely to prove less troublesome in their development. The extension of purely in silico methods to the realm of mechanistic simulation further enhances our ability to predict the impact of physiological and biochemical process on drug absorption and bioavailability. 

Podlogar, B. L., Muegge, I., Holistic in silico methods to estimate the systemic and CNS bioavailabilities of potential chemotherapeutic agents, Curr. Top. Med. Chem. 2001, 3, 257-275. 

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. 

De Groot, M.J., Kirton, S.B. and Sutcliffe, M.J. 2004. In silico methods for predicting ligand binding determinants of cytochromes P450. Curr. Top. Med. Chem. 4 1803. 

In which the terms Ha refers to the number of free electron pairs, MW is the molecular weight, and clogP is the computed lipophilicity. While this method could be stated to be "partially in silico" because it utilizes some chemical descriptors, the need for in vivo animal data and their dominance in the individual terms really makes this approach more of an animal-human correlation than an in silico method. Finally, in the same report, the authors describe a regression based solely in animal data. Overall, the performance of these... 

In silico methods able to highlight the most likely position(s) for conjugation may facilitate the development of new molecular scaffold with decreased U GT sensitivity, thus making the compounds more resistant to UGT conjugation. This may be another route for the development of more effective compounds, made possible by additional structural information on UGT enzymes available (Figure 12.2). 

The predictive performance of majority of the log BB models developed so far is 0.4 log units, despite the great diversity of molecular descriptors employed and the variations in the composition of the training sets. This seems like a large error in comparison to the range of log BB determined by experiment ( -2 to +1.5, i.e. 3.5 log units). However, it should be remembered that the experimental error in log BB measurements can be around 0.3 log units, and so this value provides a limit to the accuracy of in silico methods. 

There are a number of techniques used for target identification. Radioligand binding was a common technique until recently. Now DNA microarrays, expressed sequence tags, and in silico methods are used. 

Expressed Sequence Tags and In Silico Methods Expressed sequence tags (ESTs) are short nucleotide sequences of complementary DNA with about 200-500 base pairs. They are parts of the DNA that code for the expression of particular proteins. EST sequencing provides a rapid method to scan for all the protein coding genes and to provide a tag for each gene on the genome. 

Animal Tests, In Vitro Assays, and In Silico Methods 158... 

ANIMAL TESTS, IN VITRO ASSAYS, AND IN SILICO METHODS... 

The use of animals for pharmacological and toxicological studies has yielded invaluable information for drug development. However, many drug candidates failed in Phase I and II clinical trials because the animal models were insufficient to represent human systems and functions for some drugs. Efficacy and acceptable toxicities derived from animal models were not replicated in humans (Exhibit 5.8). In recent years, the direction in development of drugs has shifted toward the use of ex vivo, in vitro assays and even in silico methods. Nevertheless, some tests must stiU be confirmed in animals. 

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