Build and cluster diverse 3D libraries

Cresset Discovery Services (CDS) worked with BioBlocks to analyze their fragment library to maximize coverage of 3D chemical space. As part of the project, we developed an innovative clustering method that made it possible to assess the 3D similarity across their virtual database of over 1.5 million fragments.

The goal of the project was to help BioBlocks build the maximum 3D diversity into a fragment library of manageable size from a starting pool of over a million compounds. Existing techniques would have required an infeasible amount of computing power, so CDS developed an entirely novel rapid clustering method especially for the project. The solution was still extremely computationally challenging, but we were able to use our expertise in distributing calculations to the cloud to deliver the results that BioBlocks needed on time and within budget.

“Working with Cresset has been a positive experience from start to finish,” said Warren Wade, VP of Chemistry at BioBlocks. “Because our fragments are designed to be new chemical matter, they challenged the limits of existing structural descriptions. Cresset worked closely with us to overcome these limits and produce a high value compound set”.

The final result was a 3D fragment library that contains a significant number of compounds with novel core structures that are now viable candidates for fragment screening. BioBlocks envisions this Comprehensive Fragment Library to be a drug discovery tool available only to collaborators who will be able to leverage this new chemical space for their lead discovery programs. Hits from the library are entry points to BioBlocks’ collaborative medicinal chemistry processes, developed to increase the probability of generating commercially viable leads.

3D Similarity-based clustering workflow
3D similarity-based clustering workflow

Read more about this project: Large scale compound clustering in 3D.

Contact Cresset Discovery Services to find out more about how we can help you design large scale libraries for your project.

Develop bespoke software

Cresset software focuses on novel methods to discover, design, perfect or view compounds and their data in easy to use applications. Our applications are firmly founded in the experience of our customers and the most common problems that they face. However, our development expertise is not limited by our applications. We have an excellent track record of delivering novel scientific plugins, command line applications and workflows that go beyond our commercial offerings.

Custom integration

Many customers have extensive in-house computational chemistry tools that their chemists appreciate and derive value from. They like to access the unique benefits of Cresset software from within their existing solutions. In this situation Cresset Discovery Services (CDS) can develop software that is seamlessly integrated with the customer’s existing framework. From viewing our excellent electrostatic interaction potentials to detecting 3D activity cliffs we have the expertise to plug Cresset directly into their world.

Unique science

Customers regularly approach us with specific workflows, or novel approaches for which they require a truly bespoke solution. We can either develop bespoke software with an exclusive license, or co-develop novel methods for the customer to their requirements, before developing it for a wider commercial market. In either case we use our extensive experience of creating software for chemistry workflows to deliver usable, stable and functional solutions that solve the customer needs.

“Bespoke software gives customers access to Cresset software without having to change their software environment.”
Dr Martin Slater, Director, Cresset Discovery Services

Case study

Cresset were recently asked to develop a tool that could look at a customer’s SAR data and prioritize new molecules for synthesis based on the information that they would add to the project, as well as potential for activity. The outcome of this work was a ground-breaking 3D-QSAR application. As part of the customer agreement, Cresset went on to commercialize the application as Activity Atlas, which is now a component of Forge.


If you have a situation that requires a novel solution, get in touch for a free, confidential discussion to find out how Cresset Discovery Services can work with you to develop a bespoke application.

What’s in the CDS virtual screening toolbox?

Cresset is very well known for providing fast and accurate ligand-based virtual screening through Blaze. We have now added the Lead Finder docking engine to our virtual screening toolbox, giving Cresset Discovery Services (CDS) the most comprehensive virtual screening capabilities available anywhere in the industry.

Based on an informal survey of our contacts and customers, I estimate that something like 50% of all current pharma SME projects are ‘structure enabled’. Lead discovery and lead optimization are driven through the use of in-house structures, public structures (typically from the PDB) and homology models. These structures inform lead optimization programs by explaining observed SAR and providing feedback and a detailed context for the design of further analogues.

CDS routinely uses the Cresset software Blaze for ligand-based virtual screening. Although we had access to structure-based methods, we are pleased to have brought Lead Finder in-house, giving us full capability in conducting ligand-protein docking.

Ligand-based virtual screening with Blaze

Virtual screening with Blaze remains one of the most consistently requested projects for CDS. What makes Blaze extremely useful for our customers is:

  • Virtual screening is probably the only way to really sample adequate chemical diversity
  • Virtual screens are far more cost effective than wet HTS
  • Excellent enrichments can be achieved
  • The chemotype diversity in the output is second to none.

Blaze also relies on two very simple premises:

  1. A bioactive conformation encodes, in its shape and electrostatic field, both the properties, recognition features and solvation pattern optimised for interaction with its protein target site.
  2. A molecule conformation with increasing ‘shape and field’ similarity to that bioactive conformation has an increasing probability of also being active.

So, the key determinants of real activity obtained from hit lists (other than was this truly the ‘bioactive conformation’?) is often just how relevant and what distribution that hit conformation has in the population. This is fundamentally why our ligand-centric screening invariably works extremely well. Given that a molecule can adopt a similar shape, and project the same electrostatic patterns, from a completely different chemical architecture, leads to a very diverse output.

Structure-based virtual screening with Lead Finder

The Lead Finder software has been developed to provide cutting-edge docking for an array of typical tasks, from high-throughput virtual screening to best-in-class prediction of bioactive conformations to accurate prediction of binding energies. In combination with the companion Build Model protein preparation tool, Lead Finder has been shown to match or outperform the historically leading docking solutions.

When preparing ligands for virtual screening in Blaze, CDS scientists use modeling to help define the best ‘hand-crafted’ estimate of a bioactive conformation, based on the widest data for any given system. We apply the same care to exploring and preparing protein targets prior to structure-based virtual screens. We take advantage of three main approaches. Firstly, Lead Finder includes the excellent Build Model protein preparation tool. Secondly, we are privileged to be able to model proteins and ligands using the same proprietary XED force field used to give the accurate electrostatics that all Cresset software is based on. Finally, at CDS we have access to the latest Cresset software that is still under development. This gives us capability to provide protein electrostatic field maps and water analysis, providing a very reliable starting position for structure-based virtual screening.


Lead Finder uses a stochastic ligand sampling workflow, with conformations generated on-the-fly, and a genetic algorithm for processing these into pools of the best docking poses. Multiple interaction grids are generated from the protein target and combined to define a scoring system for poses. More importantly, the scoring method has been shown to outperform some of the more conventional docking engines currently available commercially.

Structure-based or ligand-based?

What are the advantages of having structure-based and ligand-based virtual screening?  And how do we choose which is the best approach for a project?

Ligand-based virtual screening is less computationally intensive, making it a preferred option when there is a known ligand available. An average protein of 400 amino acids has over 20,000 heavy atoms and 9,600 bonds and in excess of 50 charges, making it a more challenging system to model.

However, even when there is a known ligand there are some situations when a ligand-based virtual screening is not viable, such as when the known ligand does not exploit all the interactions available in an active site or when a protein has an unattractive orthosteric site and attractive allosteric sites with no known ligands. In these cases, we prefer to use a structure-based method.

In the case of protein-protein interaction sites and protein-DNA/RNA sites, Blaze can take DNA and protein fragments as a template in place of a ligand. However, it is useful to have a structure-based approach available for comparison.

In fact, we often find it useful to combine different virtual screening techniques. In lead discovery, one of the key requirements for virtual screening is to maximise the diversity of hits returned.  All virtual screening techniques, be they ligand-based or structure-based, are probabilistic techniques in that they may be used to increase the likelihood of getting hits from a wet screen. No technique guarantees to give absolute binding energies (at least not in the context of virtual screening on any realistic size of screening library), but they do give good rank ordering of compounds and can, therefore, be used as a means of selection and prioritisation.

Ligand-based techniques, whether 2D or 3D, are algorithmically distinct from structure-based techniques such as docking and, therefore, give different rankings to compounds. Different approaches return different hits and the results can be combined into an enriched final list.

Combining the results of structure-based and ligand-based techniques provides further diversity, leading to better hit rates and more interesting hits.

A one-stop shop for virtual screening

Through combining the strengths of Blaze in the ligand-based world with Lead Finder for docking, CDS now has the most comprehensive virtual screening capabilities available anywhere in the industry. Both Blaze and Lead Finder are available to purchase as software or as a service through CDS. CDS is truly now a one stop shop for virtual screening and indeed very much more.

Download a free evaluation of Lead Finder or access the Blaze demo server.

A new breed of CRO

Cresset Discovery Services (CDS) is a new breed of CRO. This is evident in two core principles that guide our work.

The first is to use excellent in silico methods to aid small molecule discovery and design.

We believe that computational chemistry tools provide intelligent short cuts, enabling us to select ‘20% of compounds that count’ to progress to the next stage of design or optimization.

Computational techniques also give an extra level of insight to chemistry and biology. In the absence of a crystal structure, computational methods are the best way of deducing information about the protein target and the likely active conformation of the ligand.

Unlike traditional serial and parallel techniques, computational design allows for iterations, meaning that conclusions can influence thinking and the next stage of experimental design.

A new breed of CROThe second principle that informs our working style is our partnership approach. Our expertise is in silico work and we create synergy by working with others who are experts in their own field. While we can recommend partners, you can also ask us to act as the project manager – sub-contracting work such as procurement, X-ray crystallography, modeling and synthesis to our partners. This makes the process seamless for you as you then just have one point of contact and one invoice to process. The following examples demonstrate how this works in practice.

Delivering plated compounds

The results of a virtual screening experiment are a list of compounds to be purchased for biochemical screening. Rather than receiving a list of potential compounds to purchase, you can ask us to take the next step and carry out the procurement for you.

We have preferred suppliers for procurement and the delivery of plates. This gives you one point of contact, saves you the logistical headache of working with multiple suppliers and takes care of any customs considerations for you.

More than that, it means that we can use our insight into the results to make the best possible substitutions if a compound is unavailable or out of your budget. Further information: Managing the procurement process to deliver plated compounds.

Chemistry and crystallography

A current project involves working out how the 3D bioactive conformation of active molecules interacts with the target protein. Essentially, we are doing some protein detective work. CDS have carried out some X-ray crystallography to check the molecules the customer had. We will then go on to design new molecules, get them made, do the crystallography and get the chemistry done with our preferred suppliers and partners.

Our chain of partners means that we can manage your discovery process from target validation and identification, finding a molecule, synthesising it, getting it tested and doing first stage trials.

Contact us today to work with Cresset Discovery Services: A new breed of CRO.

Engaging with Cresset Discovery Services

Cresset Discovery Services (CDS) offers bespoke in silico services for small molecule discovery. We do a lot of work in drug discovery and optimization for the pharmaceutical industry but we also work extensively in agrochemicals, flavors, fragrances – in fact, in any industry that involves work with small organic molecules.

This post explains the process that we go through when customers work with Cresset Discovery Services, from the first contact to the final deliverables.


At the enquiry stage we talk with customers about their requirements in general terms to get an idea of whether we will be able to help them. The answer is usually yes, but we will certainly let you know if we think that our approach would not be the best match for your project.

These initial discussions will involve members of both our sales team and the scientific team. Everything at the enquiry stage is free, but the discussions will not be at a great depth since confidential details cannot yet be shared.


Once both sides have agreed to proceed, we exchange confidentiality agreements and can then get down to the details. The customer will share their confidential data and CDS will prepare a detailed proposal of the work they will carry out.

This stage will involve a detailed meeting to gather the data and another to present the proposal. The proposal will include full details of pricing and milestones. If the work is a collaboration, then all partners will be involved at this stage.


Close collaboration is key to any successful project. Depending on the size and complexity of the project, there may be several long meetings at the start of the project. These could involve many members of the customer team. The goal is to focus on the project and to scope out exactly what needs to be achieved.

Work then moves to the details – for example, what to do, with which molecules and which conformations. This could involve conversations several times a week until everything is in place to run the study.

Frequent reviews take place throughput the project between the customer and CDS. Each customer has a personal point of contact who remains consistent throughout the project.

At each stage of the project there will be several conversations to make sure that the customer is getting exactly what they wanted. These will be tied in to agreed milestone reviews and deliverables.

Project deliverables are likely to be available through the project, not only at the end. No matter when they are delivered, the approach remains the same: we make sure that the customer gets the maximum value out of the results.

For example, typical results for a large screening project with multiple compounds may be between 10,000 and 20,000 hits. But CDS will make sure that the customer gets more than a list from the project. We will always ensure that the customer fully understands and can interpret the results in the context of the project in order to get the best out of them.


No project is complete without a project review of what went well and what could go better. As part of this process we agree the next steps, which could range from a follow-on project, to advice on the next research steps.

Many of our customers remain customers for the long term. In fact, when we do lose a services customer it’s usually because they have decided to buy our software and hire a computational chemist to work full time. This case study describes how we helped one customer to hire and train computational chemists. Even then, customers still come back to us for projects if they need the extra resource.


Contact us today to start the process of working with CDS.


Identifying possible protein targets

An academic group had identified a molecule that was active in a phenotypic assay. Due to its similarity to other compounds, they initially thought it was acting through a known pathway. However, further work revealed it was acting through a different pathway. The challenge was to identify the protein target. They chose a computational method and outsourced the project to Cresset Discovery Services (CDS).

A computational approach to identifying protein targets

There are a number of ways to go about identifying possible protein targets. The biological route is the standard method of trying to de-convolute the target from the cellular context. However, it involves a lot of time and work. Taking a computational approach can be a very efficient shortcut that narrows the search down to a few likely candidates.

The academic group choose to take the computational route and they decided to outsource this sophisticated project to CDS. Cresset was the ideal choice for a number of reasons.

The cost and time advantages of outsourcing

Firstly, it was far quicker and cost effective to outsource the project rather than trying to do it in-house. To do the work in-house would have needed to recruit an expert and to purchase the software and hardware. There would have been steep learning curves for using the software and methods. Added to this, they would potentially have been left with these overheads at the end of the project.

By contrast, for an outsourced project CDS supplies both the expertise and the infrastructure. This makes it far quicker to get up and running. It is also far more cost effective since the resources are only paid for the duration of the project.

Choosing partners who have the right expertise

Added to these advantages, CDS has specific expertise in this field. Our software calculates the interaction potentials of molecules by analysing their shape, electrostatic fields and hydrophobicity relative to atomic probes. These values are used to create a unique representation of

“This outsourced project was a very cost effective way of cutting down the list of potential targets”

molecules, making it possible to build up a ‘protein’s eye view’ of a compound. This gives a quantitative basis for comparing compounds based on how they are likely to interact with a protein.

We had already encoded the PDB ligands into Cresset field space, which translated to a head start in identifying the possible protein targets.

Carrying out the work

CDS took the active molecule as a starting point and found a number of conformations for it. We used the field patterns to search the PDB for similar molecules in order to find potential pharmacological matches. These matches revealed which proteins were worth investigating further.

From this work, CDS provided a list of potential targets to the customer. The academics worked through this short list in order to identify the actual target. This outsourced project was a very cost effective way of cutting down the list of potential targets and was certainly far more efficient than taking a purely biological route.


Contact us today to find out how Cresset Discovery Services can use their expertise to help with new approaches for your project.

June 2016 newsletter

Using services to evaluate software

Martin Slater, Director of Cresset Discovery Services, explains an innovative alternative to running in-house evaluations. By using services to evaluate software you can try the software on your own project data, saving you time and resource.

Analyze SAR and property data

Analyzing SAR and property data is a core expertise for Cresset Discovery Services. We have experience working with a wide range of different targets, including fragrances, flavors, standard pharmaceutical reagents and anti-fungal agents.

Presentations from User Group Meetings

The Cresset 2016 North American and European User Group Meetings included presentations and workshops in Cambridge, MA and UK respectively. A large and diverse group of scientists gathered to share ideas and experiences in the latest computational approaches to the design and optimization of small molecules. See workshop content plus presentations we have permission to publish.

Flavors, fragrances and force fields: Using pharma methods to sniff for substitutes

Computational methods that analyze how drugs interact with protein targets are also effective for flavor and fragrance molecules. Read how to use pharma methods to sniff for substitutes, as published in Chemistry Australia.

Lead Finder: Protein-ligand docking

As announced by press release earlier this month, Cresset are pleased to be the exclusive global distribution and support partner for BioMolTech’s Lead Finder protein-ligand docking software.

We’re hiring

Senior Scientific Consultant

We are seeking a full-time Senior Scientific Consultant to work within Cresset Discovery Services. Reporting to the Director of Discovery Services, the job holder will be responsible for the delivery of outsourced discovery projects to Cresset’s growing base of clients.

Analyze SAR and property data

Analyzing SAR and property data is a core expertise for Cresset Discovery Services (CDS). We have experience working with a wide range of different targets, including fragrances, flavors, standard pharmaceutical reagents and anti-fungal agents.

Our XED force field analysis of molecules gives you unique insight into the source of activity of your molecules. When we combine this with state of the art data analysis tools you can be sure that you are getting the best possible value from the data you own.

Usually customers come to us with a chemical asset. Their immediate objective may be to optimize a molecule to its maximum potential, or come up with a backup chemotype. Whatever the goal, they need to be able to understand the system and gain the maximum amount of information from it so that they can exploit it to the fullest extent.

A comprehensive analysis of SAR and property data is a fundamental prerequisite to most of the other work that we do. Whatever the project, we will start by looking at the activity data along with any known target information, such as sequence information or X-ray data. We investigate the different chemotypes and essentially get to know the project. For example, virtual screening often starts with some field based analysis of the active molecules to define the bioactive conformation. This analysis is fundamental to any computational chemistry work.

Gain new insight by working in 3D

Cresset scientists work in 3D. Moving from a 2D to 3D structure always reveals something new about a project and it usually gives very helpful insights. In order to know how to translate from 2D to 3D it is vital to understand the system. For example, one key determinant in finding a bioactive conformation is the inherent flexibility of the active molecules.

Get the best possible value from the data you own

Maximize the value of your molecular data

A customer purchased our expertise to get the most from their molecules.  They had 1,000 molecules in their active set and were looking to understand and extract the most useful information from that data. The fields, in other words the electrostatics of molecules, are mostly invisible to most software packages which typically look at H bonds and features rather than the overall shape. However, some quite subtle interactions come from the electrostatics and shape of the molecules, such as the electrostatics in aryl and hetero aryl rings, which are dependent on specific substitution.

In this project we were able to find a binding hypothesis that interpreted how their molecules were likely to be interacting with the protein target. This was a great help to the customer’s subsequent design rounds. We also carried out a more traditional sequence alignment based analysis, which backed up the binding hypotheses with specific mutations to conduct. This analysis supported the binding hypothesis.

This collaboration is ongoing. As a result of the proven value of our work we have carried out many additional projects with this client.

Contact us for a free, confidential discussion to find out how Cresset Discovery Services can help you to get the best possible value from your SAR and property data.

Using services to evaluate software

Evaluating new computational chemistry software requires a significant investment of time. No matter how helpful the sales team is, nor how many demonstrations you have seen, what really counts are the results you get when you try the software out on your own project data. And this is what takes the time.

An innovative alternative to running in-house evaluations is to commission a short services project from Cresset Discovery Services (CDS). We are experienced in carrying out projects using customer data so that you can free up your time to evaluate the results.

Try before you buy

Recently, a small pharmaceutical company took up this option with CDS. They had their own computational chemistry group and their own field based software that they used for virtual screening, docking and other tasks. Cresset software was of interest to them, but they weren’t going to buy it without trying it and they couldn’t spare the people to carry out a full evaluation. So they commissioned a trial project with CDS.

The computational group prepared a protein-ligand binding interaction and asked CDS to run a virtual screen on it. Rather than just go ahead and run the screen, the first step for us was to check the preparatory work. Based on this, we were able to suggest that they optimize the conformation slightly based on evidence from crystallography. This helped to refine the search, which maximized the success of the screen.

After reviewing the results they bought Blaze for virtual screening, plus remote access to our server, enabling them to use Blaze Cloud for remote virtual screens.

Outsource an on-site evaluation

Another company that didn’t have time to evaluate software themselves also wanted us to do a services evaluation project. However, in this case they didn’t want their discovery data to leave their site. As a result, CDS arranged for one of our consultants to carry out the work at the customer site.

Again, the customer was very happy with the results and actually went on to buy the full range of Cresset software to use in-house.

Services projects include software licenses

During all CDS projects we give customers a license to the molecular modeling environment Torch and other Cresset software as relevant. This enables them to see and manipulate the project data and molecules in an ideal environment. It makes it easy to communicate and explain the results and also gives them the chance to try out other options.

If you would like to run an evaluation project for any software you are considering purchasing, contact us for a confidential discussion.



Dr Martin Slater

Director, Cresset Discovery Services

Flavors, fragrances and force fields: Using pharma methods to sniff for substitutes

Computational methods that analyze how drugs interact with protein targets are also effective for flavor and fragrance molecules.

  • Applying pharmaceutical discovery methods to flavors and fragrances
  • Molecular fields and virtual screening
  • Utility of molecular fields for analyzing flavor and fragrance bioactivity
  • Pharma potential
  • When looking for new synthetic flavors or fragrances, the starting point could be an existing natural or synthetic compound, or a taste or odor receptor.

Read our article published in Chemistry Australia.

Contact us to find out more about flavor and fragrance molecule design.

Figure 2_molecular fields around two caramels_ethyl maltol and furaneol
The molecular fields around two caramels, ethyl maltol and furaneol. The surfaces show the shape (grey) and the positive (red) and negative (blue) electrostatic isopotentials, giving a ‘protein’s eye view’ of the compound.