Streamlining In Silico Profiling


Application Note

In Silico Investigation of Off-Target Effect

Streamlining in Silico Profiling
In silico techniques require exhaustive data and sophisticated, well-structured informatics tools to help scientists gain insight into crucial aspects of compound behavior, including potential off-target effects. The right research support solution can greatly streamline the process.

Profiles generated using in silico methods have many advantages over more costly in vitro and in vivo techniques. For example, fewer molecules are synthesized and cell and animal use are reduced. Ultimately, predictive, targeted R&D enables faster experiments.

Early Prediction Of Off-Target Effects Means Better Planning

Off-target effects result from a drug modulating targets other than the intended one. Knowing what effects a candidate compound might have is essential for well-informed drug development decisions. The early identification of possible off-target effects could help scientists select the best possible scaffolds for advancing through hit-to-lead and on to lead optimization. In silico compound profiling allows researchers to gain valuable information in order to plan and prioritize drug discovery and development programs. This tool is frequently used to investigate potential off-target effects. As part of the investigation into such effects, scientists will often compare profiles of compounds that are similar to a potential drug candidate in order to identify interactions. This whitepaper describes how such profiling can be performed efficiently with the data and analytical features of Reaxys® Medicinal Chemistry, using the example of a hypothetical hit structure to target the histamine H3 receptor.

High-quality scientific data facilitates accurate global compound profiling,. This is the best way to see how a molecule interacts in the pharmacological space and in later-stage ADME studies. These profiles help organizations plan and manage research programs. They can also alert scientists to potential off-target interactions or toxicity issues; provide options for repurposing drugs; and enable more definitive and better-informed go/no-go decisions.
In silico global compound profiling exploits in vitro and in vivo experimental information to produce a profile of properties for a given compound. It follows the same methodology as experimental profiling, in which a large set of compounds is screened for a particular activity and an active set is further pared down (or profiled) using specific parameters such as mechanism of action, selectivity and ADME characteristics.
Profiles generated using in silico methods have many advantages over more costly in vitro and in vivo techniques. For example, fewer molecules are synthesized and cell and animal use are reduced. Ultimately, predictive, targeted R&D enables faster experiments.

The Role Of Reaxys Medicinal Chemistry

The Reaxys Medicinal Chemistry database is organized around compounds, targets and biological activities. Each element is described and organized into logical hierarchies according to experimental protocols appearing in the literature. Taken as a whole, the information compiled by Reaxys Medicinal Chemistry creates a global pharmacology space encompassing more than 447,000 literature sources, 12,700 targets and over 29 million biological activities.

    The user interface enables scientists to:

  • Navigate this pharmacology space and conduct a variety of searches, including substructure and chemical similarity searches
  • Explore in silico selectivity profiles for targets, cell lines or compounds
  • Filter retrieved data to exclude or limit certain data sets, focus on compounds or targets, or view a complete list of citations.

The interactive Heatmap displays compound–target data in a manner allowing the rapid visualization, navigation and filtering of results based on various parameters such as activity, species, bioassay protocols, publication type and standard target classification hierarchies.
To facilitate comparisons of bioactivity data from different publications and assay types, all the data points in Reaxys Medicinal Chemistry have pX values, which are displayed and filtered through the Heatmap. They are calculated by transforming EC50, IC50, Ki, etc. into pEC50 = -LogEC50, pIC50= -LogIC50, pKi = -LogKi, etc. These are normalized values assigned to the data to enable straightforward quantification of compound–target affinity regardless of the origin of the data.
Reaxys Analysis View lets users select analysis criteria to get a sense of the relationships between results. The histograms can be set to various categories and will display the number of hits in the hitset that correspond to the two categories.