How do I turn my biology insight into a novel therapeutic?

The question that many of the people talking to Cresset Discovery Services ask is “I have discovered some interesting biology – how do I turn it into a drug?”. If this is you, then read on.

Let’s look at some of the ways that we can use in silico technology to translate your ideas into chemical tools in the first instance. Optimizing the drug-like properties of these early hit compounds will put you on the road to defining a lead series and onwards to nominating a drug candidate for clinical studies.

Finding a chemical starting point

The first step in the drug discovery journey is to find a chemical starting point, a molecule that binds to your target and either blocks or enhances its activity. Your overall aim may be to block a key point in a signalling pathway, or divert it to an alternative route.

Alternatively, you may want to prevent levels of a particular cytokine from building up or block the activity of an enzyme, a receptor or an ion channel. Don’t overlook the fact that you may already have found chemical tools that modulate your biological target – what are its physiological activators, are there any literature compounds or known drugs we can use to get you started?  What is known about the protein target? Do you have structures of your system, or are there examples of close relatives on the Protein Data Bank? Can we learn from off-target effects of other compounds or scaffold-hop from one chemical series to another to create new intellectual property.

Your next milestone faster and more cost effectively

Using computational chemistry effectively can both considerably speed up hit finding and reduce the costs of running large physical screens. The best approach to take will depend on the type of bioassay that you intend to use. For example, you can test many more compounds in a plate-based enzyme assay than you can screen in a complex phenotypic system so you need to decide whether you want to test thousands of compounds or would prefer to look at a smaller bespoke set of compounds.

In both cases, initial steps will focus on defining the bioactive conformation of one or more compounds that bind to your protein. We use these as pharmacophores to search for similar compounds that will have the same biological effect. By applying the XED force field we take a unique view of molecules which means that we can compare different chemical classes directly. This is a better reflection of how proteins ‘see’ other molecules and explains how drugs bind to sites that evolved to interact with peptides, DNA or other natural products. In summary, we are looking at the wider electrostatic and shape properties of molecules that extend beyond their atomic skeletons and are responsible for their biological properties.

Efficient virtual screening for diverse new structures

One popular option for kick starting the search for a hit compound is to use Cresset Discovery Services to run virtual screens. By using Blaze (an effective ligand-based virtual screening platform optimized to return diverse new structures) or Flare (which provides fresh insights into structure-based design) we can search a library of 20 million commercially available compounds. The output will be a list of compounds ranked by the similarity of their field point patterns to your pharmacophore. We can filter the list to prioritize compounds that have the appropriate physicochemical properties based on the nature of your target. Most importantly, this will give you a shopping list of compounds that you can purchase and test before you build significant synthetic chemistry resources in your team.


The same approach allows you to move from one chemical series to another – particularly useful when you are looking for a backup compound to fill a hole in your portfolio or overcome a deficit in your existing series.

Building bespoke libraries

You can purchase millions of compounds from chemical vendors, however, these still only represent a fraction of all possible compounds – even if we only consider molecules that are small enough to be used as drugs. Substances produced by organisms have evolved to form interactions which are not always available to off-the-shelf chemicals. Sometimes it is better to design your own library so that you can build in features that explore different regions of chemical space or mimic the properties of natural products. We can help you design libraries that move you into new areas of chemical space or focus on specific features of a molecule.

3D similarity-based clustering workflow.

Working with fragments

One approach to getting better coverage of chemical space is to work with low molecular weight compounds (<300 Da), termed fragments. Linking these together can generate larger drug like molecules, however, accomplishing this is recognized as a difficult task. Spark, a scaffold hopping and R-group exploration application, enables us to offer you a tailored solution to this problem, using fragment libraries constructed from those that occur in biologically active molecules. New suggestions for compounds to make can be built to fit the binding cavity in a protein structure. See how Spark was used to grow and link fragments.

Free confidential discussion

We have worked on hundreds of projects on different biological targets and would be happy to discuss the best approach for accelerating your assets through the pipeline. Contact us for a free confidential discussion.


Cresset to participate in the first SCI/RSC Computational Chemistry Workshop on April 10

Talking to a group of medicinal chemists at a conference over lunch raised the following question: “It’s really interesting to see all the clever things that can be done with these software tools, but could we have a meeting where we actually get to try them out for ourselves?” . With this in mind a combined team from SCI and RSC decided to organize a computational chemistry workshop where people could access software and benefit from top quality training from the creators and developers of a range of these tools, each of which address different aspects of pre-clinical drug discovery. All scientists working in this area need tools and techniques for handling chemical information but it is difficult to get an opportunity to try out more than one package at a time and we would all relish a helping hand to get up and running as quickly as possible.

Cresset is always keen to introduce new people to the concept of fields and to demonstrate the ways in which they can be used to design biologically active molecules. We are very happy to welcome Giovanna Tedesco, Senior Product Manager at Cresset, who will present on:

Next generation structure-based design with Flare

Learn how simple structure-based design can be within small molecule discovery projects. The workshop will cover ligand design in the protein active site, Electrostatic Complementarity™ maps and scores, ensemble docking of ligands with Lead Finder, calculations of water stability and locations using 3D-RISM, energetics of ligand binding using WaterSwap and use of Python extensions. Applications you will use: Flare™ , Lead Finder™.


Participants will be able to pick 4 out a possible 6 workshops over the day, choosing from sessions covering data processing and visualization; ligand and structure-based design, or ADMET prediction. These are all areas that chemists working in the pharmaceutical, biotech, life sciences and agrochemicals sectors engage with every day. Full details of all workshops are available from SCI and slots will be assigned on a first-come-first -served basis. Most importantly, all software and training materials required for the workshop will be provided for attendees to install and run on their own laptops and use for a limited period afterwards. This will give everyone the chance to take what they have learnt back to their own organisations and try out their newly acquired skills on their own data.

When: April 10, 2019

Where: The Studio, conveniently located next to Birmingham New Street Station, Birmingham, UK

Registration is open and the early bird price of £30 (£40 for non-SCI/RSC members) is available till 27th February. Financial support to cover travel and registration is available for students on application.

I hope you are able to join us for a unique opportunity to get to grips with a wide range of tools and concepts which you can use in your own research.

Find out more and register now.

Caroline Low, PhD, FRSC CChem

SCI Scientific Organizing Committee member and Cresset Discovery Services consultant