Modelling in silico

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... 

First Model In Silico Model for Deducing Drug Resistance Mechanisms... 

Second Model In Silico Model to Combat Resistance... 

Text mining of literature for all biological context for target Use in silico model to identify potential issues Gather data for in silico prediction (local model) In silico prediction (local model) Set up in vitro screen to select a safer compound Predict relevance of such toxicity in human... 

In Silico Literally in the computer. It can be used to screen out compounds which are not druggable. Narrower terms include in silico biology, in silico modeling, in silico proteomics, in silico screening, and so forth. 

To conclude, the future drug development paradigm that is built on human biology-based in vitro models, in silico tools, and accurate prediction of human ADME and exposure is expected to provide a decrease in late-stage development failures and withdrawals of marketed drugs, faster timelines from discovery to market, and reduced development costs and larger number of patient-centric, safer therapies (Fig. 7.1). 

In Vitro Models In Situ and Ex Vivo Models In Vivo Models Engineered Mouse Models In Silico Modeling... 

To infer analyte ion structural details, IM-MS-determined collision cross sections are typically supported by complementary computational studies. Although the specific procedural details for comparing empirical cross-section values with those obtained by computational techniques varies by laboratory, the general framework for comparisons consists of five steps (i) generation of model in silico structures, (ii) exploration of the conformational landscape (e.g., by molecular mechanics/molecular dynamics (MM/MD) and simulated annealing protocols), (iii) determination of modeled structure colhsion cross sections (typically via MOBCAL developed by Jarrold and co-workers ),... 

The reliability of the in silico models will be improved and their scope for predictions will be broader as soon as more reliable experimental data are available. However, there is the paradox of predictivity versus diversity. The greater the chemical diversity in a data set, the more difficult is the establishment of a predictive structure-activity relationship. Otherwise, a model developed based on compounds representing only a small subspace of the chemical space has no predictivity for compounds beyond its boundaries. 

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. 

Defranoux NA, Stokes CL, Young DL, Kahn AJ. In silico modeling and simulation of bone biology a proposal. / Bone Miner Res 2005 20 1079-84. 

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. 

Van de Waterbeemd H, Gifford E. ADMET in silico modelling towards prediction paradise Nat Rev Drug Discov 2003 2 192-204. 

The tools for in silico toxicology are broadly applied in the drug development process. The particular use of the tools is clearly context-dependent, which includes the quality of the prediction and the applicability domain of the model. 

Once candidate molecules have been selected, there is an increased possibility for more in-depth in silico studies for toxic effects. These could, for instance, take the form of attempts to design out toxicities from a fundamental point of view, or may involve de novo modeling efforts. For instance, just as drug activity is optimized by QSAR, toxicity could also be minimized. 

Because of its convenience and good patient compliance, oral administration is the most preferred drug delivery form. As a result, much of the attention of in silico approaches is focused on modeling drug oral absorption, which mainly occurs in the human intestine. In general, drug bioavailability and... 

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