Addressing toxicity risk when designing and selecting compounds in early drug discovery
Summary In this article, ‘Addressing toxicity risk when designing and selecting compounds in early drug discovery‘, we discuss the application…
What is Derek Nexus?
Developed by Lhasa Limited, Derek Nexus is an expert-knowledge based system that draws on over 40 years of research to provide manually curated structure-activity relationships for a broad range of toxicology endpoints including mutagenicity, genotoxicity, carcinogenicity, hepatotoxicity and skin sensitisation.
When presented with a query compound, Derek Nexus uses a combination of rules and structure-activity relationships to provide a prediction. If Derek believes there is a toxicity risk associated with the compound, it will outline the endpoint of concern, provide a level of likelihood, highlight the proposed toxicophore (the part of the structure associated with toxicity) and provide a broad range of supporting information such as mechanistic rationale, references and literature examples.
What is the StarDrop Derek Nexus Module?
StarDrop provides access to state-of-the-art chemical visualisation and analysis tools, assisting you in decision making, both in hit-to-lead and lead optimisation. This core functionality can be extended through the use of optional modules, including the Derek Nexus Module.
It’s implementation within StarDrop is limited to outlining endpoints of concern, providing levels of likelihood and highlighting the proposed toxicophores (using StarDrop’s Glowing Molecule). The broad range of supporting information provided by the full Derek Nexus package is not available.
Which system is best for me?
Well that depends on what you are trying to achieve. Let’s look at 2 key use cases for in silico toxicology prediction:
1. The assessment and control of DNA reactive (mutagenic impurities)
Under the ICH M7 Guideline a computational toxicity assessment can be performed using two complementary (Q)SAR prediction methodologies to assess the mutagenic and carcinogenic potential of actual/potential impurities within an API. Such a strategy enables organisations to significantly reduce the number of impurities that they have to purify/synthesise and then test, resulting in significant savings.
As an expert-knowledge based system Derek Nexus provides one of the two complementary methodologies. The second methodology should be statistical-based and Lhasa Limited can help here too as they also develop Sarah Nexus.
When assessing impurities in this way under ICH M7, the results obtained from the predictive methodologies must go through a process called expert review i.e. it’s not enough just to say both my predictive methodologies have no concerns. Instead the results must be reviewed in detail for each impurity and supporting evidence provided for the conclusion.
So if you want to use the Derek Nexus methodology for the assessment of impurities under ICH M7 then you would need to use the full Derek Nexus package from Lhasa Limited. The StarDrop Derek Nexus module lacks the broad range of supporting information making it unsuitable for the expert review process.
2. Prioritising compounds with a lower chance of causing toxicity early in the drug discovery process
Toxicity remains a major issue in the development of new drugs, leading to attrition and associated costs. Including an in silico assessment of toxicity early in the drug discovery process can help reduce attrition and enable you to focus projects on “safer” chemistry.
But safety is just one aspect of what makes a successful drug. Good drug candidates need to have an optimal balance of potency, solubility, metabolic stability, absorption and safety. StarDrop’s probabilistic scoring approach to multi-parameter optimisation combined with its comprehensive range of predictive models, including those from the Derek Nexus module, enables you to assess all of these factors and quickly identify chemistries with this optimal balance.
Furthermore, when used in combination with the Derek Nexus module, StarDrop’s glowing molecule will highlight any regions of compounds that triggers a toxicity alert. This interactive visualisation allows you to guide modifications and explore strategies to reduce the likelihood of toxicity.
Conclusions
So if you’re looking to lower the chance of toxicity in the drug discovery process, and identify compounds with an optimal balance of properties, then using StarDrop with the Derek Nexus module would be a great solution.
That’s not to say that the full Derek Nexus package cannot be used in discovery to flag toxicity risks, it can. But it only deals with toxicity in isolation and offers very limited functionality in terms of visualising and further analysing your compounds and any associated data.
Think StarDrop could be right for you?
We would love to show you how StarDrop can help your drug discovery projects. Complete the form and a member of the team will get in touch to arrange a personalised demo for you.
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About the author
Scott McDonald, MSc
Scott is a Business Development Manager at Optibrium, where he helps scientists make scientifically robust decisions through software solutions that enhance drug discovery and development. He works with clients to leverage Optibrium’s products.
With over 17 years of experience in the life sciences industry, Scott holds a Master’s degree in Chemistry from the University of Salford.
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