Consulting services as try-before-you-buy option

Customers often use Cresset’s consulting services to evaluate our techniques before they buy the software

As CEO of a software and services company, I am sometimes asked whether Cresset is a software company with added consulting services, or a consulting company that has turned some bespoke software into products. The easy answer is ‘a little of each‘, but the reality is more subtle and complex.

Over the 20 years that I have been involved in drug discovery, the R&D structures, methods and philosophies have changed greatly. Combinatorial chemistry and high throughput screening were once the brave new worlds; now we are looking to ‘omics for the future. There have been swings between internal and external research and between biology-led and chemistry-led research. Over the last five years the emphasis has been on externalizing early-phase discovery, with large pharma companies concentrating more on in-licensing then developing compounds through to market launch.

Through these changes, one thing has remained constant: any company that provides support and services to the industry must focus on flexibility. In other words, in order to stay useful we need to be adaptable! So, ‘Is Cresset a software or services company?’ The answer always has to be ‘Yes’!

The focus at Cresset is always to develop the best scientific methods and technologies to help scientists to make better decisions for drug discovery. How we deliver this depends on our customer. We see consulting services as a direct adjunct to our software products, and vice versa.

One very direct example of the synergy between the two sides of the business is our ‘try-before-you-buy’ service offered by our consulting team. Clients often approach us with an interest in our software products, but then use the consulting services as a way of evaluating Cresset’s techniques before they buy the software. This helps them to understand how our technology will fit with their R&D workflow.

The ‘try-before-you-buy’ service has a number of benefits. Internally, it is often easier to justify the purchase of consulting services to solve a problem, rather than asking for the budget to evaluate yet another piece of ‘vital’ software. The consulting service takes the place of the evaluation, but is focused on real research problems. The impact of the science behind the software can also be evaluated somewhat independently of any issues surrounding optimal use and set-up of the tools.

From our side, engagement in a consulting project provides a great way of understanding the specific problems a customer is trying to solve, or the specific workflows which they have within R&D. This also helps us to see how the software products can be optimally aligned to those processes and challenges.

This is a true win-win situation. If the consulting project goes well, the customer has progressed a project and we have a happy new customer. On the other hand if the results are not positive, we are all in a better position to understand the reasons behind this. We can then explore alternative approaches to get the maximum benefit, even from a negative set of experiments.

Over the last couple of years I have seen a number of successful examples of our ‘try-before-you-buy’ approach. The customer has ended up taking a combination of consulting services and software products. In a couple of instances the actual choice between software and service has changed from year to year. In all cases I like to think that the customers appreciate the flexibility which is provided to them by their ‘software and services’ partner.


Dr. Robert Scoffin, CEO was in conversation with Sue Peffer, Marketing Manager.

Contact us to find out how try-before-you-buy can benefit your organization.

Delivering high quality library design

Libraries of chemical compounds are the lifeblood of modern drug discovery programs. The quality of library design can determine a project’s success or failure.

Both molecular modeling and cheminformatics techniques are important for the production of chemical libraries. The Cresset Consulting Services team has the analysis and design experience that is vital for the delivery of successful chemical libraries.

Different types of library design

Library design as a concept is not new, but it only became a popular paradigm in drug discovery a decade or so ago. Over time the field of library design has split to encompass two main type of library, both of which are commonly used by medicinal chemists for their drug discovery campaigns:

Diverse

  1. Diverse compound libraries for the discovery phase
  2. Diverse lead-like libraries for the discovery phase
  3. Diverse fragment libraries for fragment based drug discovery

Knowledge-based

  1. Focused libraries for the discovery phase
  2. Libraries for the lead optimization phase

Modern drug discovery now rarely proceeds simply via the classical route of making serial changes and acting on the output of testing. Rather, activity is explored using SAR explosions at discrete points in the process.

Designing a diverse library

Diverse sets of compounds – be they drug-sized, lead-like or fragments – are usually created by selecting compounds from a greater pool using some measure of diversity on the pool. The pool could be commercially available compounds (singles or libraries), internal collections or synthetically accessible library space. Often a combination of these sources is used to get the widest possible range of compounds into the final library. In most cases the selection of compounds to include in the diverse library proceeds by using a combination of 2D similarity matrices and property calculations. This is essentially the process used by big pharma to get the most out of their compound screening file.

Although there are established methods for this, which work OK for generic screening molecules from vendors, there is no standard protocol and each company may have a different preferred set derived from the same commercially available pool.

Diverse fragment libraries

With the rise of fragment based drug discovery over the last 5-10 years a thirst has emerged for libraries containing smaller lead-like and fragment-like diversity. The type of analysis required to gauge redundancy in this case becomes tricky as the smaller the molecules become the more difficult it is to create meaningful robust measures of chemical similarity – many of the 2D similarity methods lose their discriminatory ability. Thus fragment libraries or lead-like libraries may require special treatment.

We have become interested in using our own description of molecules – their shape and electrostatic character – to describe compound collections. We presented some initial work in this space at the spring 2012 ACS meeting. In this blog post Tim describes how we are looking again at the diversity of compound and specifically fragment collections using the computational efficiency available from BlazeGPU.

Knowledge based library design – Focused libraries

To design a focussed library computational input becomes a critical factor. Focused libraries are inherently the result of leveraging the designs using existing knowledge. However this knowledge can be applied in different ways. Two clear approaches are common in this space, each with differing factors that dictate the course of the library design workflow.

The technique typically used by compound vendors is to filter their compound collection based on the fit of molecules to activity models that have been developed (e.g. using physical property, pharmacophore or 2D similarity models). The usefulness of the classification is entirely dependent on the details of how the model has been constructed and applied.
The alternative technique, often employed by specialist vendors and bigger drug discovery organisations, is to design novel scaffolds and substitutions to address specific biological target areas of interest. These include application of structure or ligand based designs targeting protein families or sets of related targets using medicinal chemistry principles. Unlike the filtering approach above, in this case all molecules would have to be synthesized with inherent advantages (notably IP) and disadvantages (cost) that comes with this.

The latter undoubtedly requires the greatest engagement of time and resource to provide a suitable level of insight into the problem from which to develop innovative chemical solutions.

Case study

S-adenosyl methionine (SAM) is a co-factor used as a biological methylation synthon. It is employed in a host of enzymatic methyl transferase processes which are important in a number of disease areas. In the area of Epigenetics the lysine methyl transferases ‘KMT’s are responsible for methylating lysine groups on histones – a process which mediates gene expression by changing the stability of the nucleosome.

A quick analysis of the binding conformation of SAM across the PDB (Figure 1) reveals a small number of clusters of SAM bioactive conformations are observed. The conformation of SAM found in KMT’s form a tight cluster which is distinct from the more diverse generic SAM utilising enzymes. Interestingly, the analysis shows that DOT1L, which is also thought to be a KMT, is an outlier and more closely related to the generic enzyme set than to the other KMTs.

Figure 1. SAM conformations from SAM utilising enzymes observed from the PDB

Figure 1. SAM conformations from SAM utilising enzymes observed from the PDB

Assuming we wished to pursue a SAM mimetic design as a paradigm for KMT or DOT1L inhibitor generation, then from a molecular design point of view there are a number of issues which would need to be addressed. One major issue already given is that SAM is ubiquitously used as a cofactor thus a close mimetic may have unwanted side interactions. Clearly a DOT1L SAM mimetic design will have more issues with generic SAM enzyme crossover. A design aimed at other KMTs (e.g. SMYD2) would have selectivity issues just within the specific KMT family.
Designing away from potential crossover activity could be achieved by a full SAM mimetic design since both the adenine and Met chains adopt different vectors and shapes in the different sub-classes. Alternatively, concentrating on the adenine mimetic alone, the H-bonding patterns and solvent exposure are distinct in the two enzyme sub-classes as shown in Figure 2.

Figure 2. Differences in recognition of adenine in the two ‘DOT1L-like’ v ‘KMT-like’ systems

Figure 2. Differences in recognition of adenine in the two ‘DOT1L-like’ v ‘KMT-like’ systems

This simple example shows how some background knowledge on the system can impact on the scope and potential success of any given design.

We described in our previous blog how our fragment replacement tools can be used to search for novel bioisosteric replacements – in this case using the Spark software with adenine as the molecular input you can find suitable replacements as seeds for a library. As the template is extracted from a protein context all the ideas would be generated in the same coordinate frame and thus could be visualized and assessed for fit into the protein.

Alternatively the whole SAM 3D conformation from whichever sub-class could be submitted to Blaze to search for commercial vendor molecules that fit specific field patterns from the specific SAM conformation.

Figure 3. Library design idea for a SMYD-like KMT inhibitor (Left: SAM from SMYD2 and Right: virtual molecule)

Figure 3. Library design idea for a SMYD-like KMT inhibitor (Left: SAM from SMYD2 and Right: virtual molecule)

The output of these virtual exercises, rather than being molecules to test (which is the usual scenario) would be molecular scaffolding ideas that would be potential starting seeds for a design. Ideally we would be looking for a good molecular fit to the interaction patterns (Figure 3) and especially to those which also provide appropriate synthetic vectors from which to explore the allowed variation defined from the starting binding pose.

In this case Spark has provided us with a design idea which matches well to the field patterns and interaction patterns required by the KMT SAM conformation in SMYD2 (PDB: 3S7F) and provides three potential vectors for a library: R1 for the substrate pocket, R2 for the open solvated pocket, R3 for the ribose pocket (Figs 3 and 4).

Figure 4. Interaction patterns and putative library design substitution vectors.

Figure 4. Interaction patterns and putative library design substitution vectors.

A standard protocol for constructing the library might proceed as follows:

  1. Synthetically accessible variants (i.e., commercially available building blocks) of the above library would be gathered and a method outlined, possibly involving
  2. intermediate route scouting for incorporating R2 and R3 variants first and then a final array
  3. fulfilled by elaborating R1.
  4. A virtual ‘all-combinations’ library would be constructed and
  5. the enumerated library analyzed in terms of predicted ‘drug-like’ properties [MWT, LogP, TPSA, (HBD, HBA, Rot.bnd)-counts etc]. Combinations which provide poor properties would be discarded.
  6. Chemistry validation of the synthetic route and scope for the decoration transformations would be established followed by
  7. stability studies on a sub-set before (VIII) final synthetic library construction and (IX) purification and plating (i.e., 96 well plates for screening).

Our library design service offering

Cresset computational chemists have wide knowledge of and experience in delivering projects involving all of the library scenarios described above which we are now able to offer as a service. Contact us for more information.

What does scaffold hopping mean to you?

One of the most popular requests for our consulting services team is to conduct ‘scaffold hopping’. The aim of scaffold hopping is to find new chemical structures with similar biological activity to the original by changing components of the molecule.

One issue with scaffold hopping is the phrase itself; it can mean slightly different things to different clients and can entail quite different scenarios. In drug discovery or a more general context, scaffold is usually defined as: ‘The central molecular component from which a specific combination of substituents or decorations define the interesting compounds within the series’.

It is this component that is the focus of the desired replacement or ‘hop’. The central component’s shape, electrostatic properties and vectors generally underlie the biological activity of interest, but it is the framework and combinations of decoration, defined in 2D, that hold the intellectual property.

Because the definition for protecting composition of matter under patent law relies on 2D structure and not biological activity, it is possible to take out a new patent on a structurally different molecule, despite it doing essentially the same job as an existing patented molecule. This sustains the so called ‘fast-follower’, ‘me-too’ and ‘me-better’ niche in the broader chemicals industry.

What are the strengths of virtual scaffold hopping?

The arguments for attempting ‘virtual’ scaffold hopping are similar to those already described for virtual screening, namely:

  • Scaffold hopping is an effective way of identifying new intellectual property
  • Virtual scaffold hopping is cheaper and quicker than wet scaffold hopping
  • Using computational chemistry to investigate your lead series often leads to other insights into the mechanisms of biological action.

Scaffold hopping projects take a number of different forms, but generally engage the same technology used for virtual screening, making use of Cresset’s Blaze/a> software. In this case the scaffold hop is achieved by using Blaze to search commercial compound vendor collections for a suitable ‘whole molecule’ replacement. This by definition produces new scaffolds as the output.

A second powerful software capability that we hold at Cresset allows us to explore changing one component of the active molecule at a time. This method is called ‘fragment replacement’ and is carried out using Spark. Rather than searching for commercial compounds to purchase, Spark provides ideas for new molecules that can be synthesized.

At Cresset’s recent North American user group meeting the independent medicinal chemistry consultant Alfred Ajami gave a presentation describing the use of Spark to retrospectively analyze two case studies from the bioisosteric replacement literature and to evaluate its performance in a number of projects that he has been involved with. For more information, see: Drug hunts with Spark: case studies from the literature and current campaigns to develop immunokinase inhibitors, Alfred M Ajami, DCAM Pharma Inc.

In the hands of trained users such as our experienced consulting team, both of these applications provide useful ideas for exploring new potential actives in a highly efficient manner.

Example of a field based scaffold hop from a therapeutically interesting peptide
Figure 1: Example of a field-based scaffold hop from a therapeutically interesting peptide ‘AMP1 analogue to a small non-peptide synthetic mimetic (from PDB: 2D1X: an SH3 interacting peptide active in breast cancer metastasis inhibition).
Comparison of the electrostatic field surfaces of the target and scaffold hop
Figure 2: Comparison of the electrostatic field surfaces of the target and scaffold hop from Figure 1.

When should I employ this technique?

Scaffold hopping for replacement of a central heterocyclic core is a very common workflow. In spring 2013, Tim Cheeseright, Cresset’s Director of Products, presented a detailed study on the use of Spark for scaffold hopping from the core of Sildenafil. He showed that using Spark gave comparable results to those published by Pfizer but in a fraction of the time.

Scaffold hopping is a useful technique during the discovery phase of a project when there are no starting points other than a complex natural product. We have successfully used the scaffold hopping technique during several client projects to find small molecule actives with more tractable chemistry.

In the lead optimization phase where a current chemotype has proven active against the target biological system but has an intractable liability, both virtual fragment replacement protocols and whole molecule replacement are relevant.

One clear liability for an oral drug would be if the molecule is a protein, a small peptide or a nucleotide. Because the Cresset software is not dependent on the molecular framework, the output can be a small synthetic molecule derived from whatever input type was chosen, be that protein, nucleotide or cofactor. Cresset has performed several scaffold hops from an active peptide or cofactor.

Thus it can be seen that under the term ‘scaffold hopping’ we cover a far wider scope than the usual definitions of ‘scaffold’.

The following table summarizes the main areas in which scaffold hopping can be usefully deployed for drug discovery:

Application Area Cresset Software
Hit to lead (fast follower) Blaze
Lead optimization (known liability avoidance) Blaze, Spark
Back-up series identification Blaze, Spark
Complex natural product to small molecule active Blaze, Spark
Protein – protein interaction inhibitors Blaze
Nucleotide – protein interaction inhibitors Blaze
Substrate-cofactor conjugate enzyme inhibitor Blaze, Spark

Contact us for more information about how Cresset can apply scaffold hopping to your project.

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Dr Martin Slater,
Director of Consulting

Ligand-based virtual screening as a service

“Above and beyond the physical data output, it is often the insight that is gained from the project that is the most useful deliverable.”

Cresset Consulting has been providing modeling and computational chemistry support for drug discovery projects for over a decade. We have collaborated with academics, biotechs and big pharma offering a unique blend of bespoke molecular modeling expertise and state of the art field-based modeling technology.

Over this time we have naturally covered a wide range of therapeutically relevant drug targets and also many disease areas in which the biological target was unknown. The majority of these projects have involved ligand focused virtual screening, which is the mainstay of our consulting business.

There are several reasons why our virtual screening service is so popular:

  • It is an effective means of switching chemical series to identify new intellectual property
  • It is a fast and cost effective way of testing several different hypotheses
  • Our common sense approach means we set realistic expectations of what can be delivered
  • The chemical understanding gained from our collaborative working model goes beyond the physical project results to add valuable insight to your research.

Switching Chemical Series to Find Clear IP

Intellectual property (IP) space is of paramount importance in drug discovery. It is increasingly difficult to find valid and useful protein targets for which drugs can be marketed. Consequently, many of the good biological targets are quickly saturated once they are identified. Virtual screening offers a highly efficient and rapid process for hopping from one chemical series to another, which is an effective way to find new chemical space without IP restrictions.

The Blaze ligand-based virtual screening software uses the electrostatics and shape character of known ligands to search large chemical collections for molecules with similar properties. This makes it possible to identify new chemical series and, therefore, exploit the narrow windows of opportunity afforded by IP constraints.

Field-based similarity searching of molecules is a 3D method that accurately encodes surface electrostatics and shape. It is consequently largely independent of the underlying molecular framework. The method is optimized for finding the combination of features which are more biologically relevant to the protein interaction than are present in the chemical structure itself.

A Cost Effective Way of Testing Several Hypotheses

Virtual screening approaches are vastly faster and cheaper to conduct than their traditional wet chemistry and biology equivalents. Millions of commercially accessible compounds can be run through a virtual screen in a matter of days on our moderately sized CPU cluster. An equivalent high throughput screen could cost in the order of $2m.

One clear advantage of the speed and cost of virtual screening is that several hypotheses can be tested using virtual screening. Only one hypothesis needs to provide a useful output for this cost effectiveness to be realized.

Common Sense and Integrity Mean Realistic Expectations

Claiming that virtual screening is always the answer is quite rightly met with disdain from seasoned medicinal chemists, many of whom at some point have been naively promised something which in reality could not be delivered by modeling. The cost effectiveness provided through computational chemistry is only realizable if something of value is delivered to the drug discovery program, and delivered in a timeframe in which it can be usefully employed.

In Cresset’s consulting projects we strive for a deeper understanding of each specific project and aim to offer the solution that we believe will provide the best chance of success. No modeling computational techniques have a 100% success rate, but our experience will help drive the chance of success as high as possible with our recommendations for that specific task.

If our experience and investigations suggest that we will not get meaningful results through virtual screening then we may suggest a more suitable course of action, including not doing the task! We bring common sense to all of our projects, informed by our integrity and our scientific expertise.

Delivering Chemical Insight Along with Physical Results

Cresset consulting provides a truly consultative service. By that we mean that we listen carefully to our clients throughout the project, questioning them to identify their needs and goals as clearly as possible, and working closely with them as the project progresses. This collaborative approach means that both parties gain far more scientific insight from the relationship than a simple set of virtual screening results.

We take great care in providing the results in whatever way is most helpful to our clients. We provide a variety of output files held privately and securely for each client on our FTP server. The output is frequently SDF files, PowerPoint presentations or document files, which can be full written reports if specified.

Above and beyond this physical data output, it is often the insight that is gained from the piece of work that is the most useful deliverable. Post project wind-up meetings, either face-to-face if possible or via the web, have proven particularly valuable to our clients over the years.

Find out more about Cresset’s consulting services and virtual screening, or contact us to find out how we can add value to your projects.

Martin_Smart_B&W_150x150_2

Dr Martin Slater,
Director of Consulting

Great consulting for great business returns

Concluding this series of blogs, Dr Martin Slater, Director of Consulting services at Cresset, talks about what makes a great consulting project.

So far in this blog I’ve talked a lot about project based work that Cresset has undertaken for clients. This gives our customers access to our expertise without the cost and risk of hiring an in-house computational chemistry team.

In general Cresset does not benefit from downstream royalties on projects, although we have carried out some more collaborative drug discovery programs, particularly with charity and academic partners, in which we have retained some IP rights. In the majority of cases though we offer a very simple fee-for-service model in answering very specific questions and addressing key issues in the discovery and early development phases of a new drug.

In response to customer feedback, Cresset consultants have developed a very flexible model of working that we call ‘CompChem on demand’. Clients buy the number of days they need and then call on us to work for them anytime within the next year. We are often called in to help overcome obstacles on particular projects, and we’ve found that this model often leads to longer term collaborations.

Of course, different clients prefer different consulting models and we try to be as flexible as we can. As such, we even rent out our software on a per project basis. The scientists get access to state of the art software tools, but only pay for what they use. This model is particularly popular with contract research organizations since it makes it easy to bill clients for product usage.

In other words, you can hire the software for your chemists to use, you can hire our consultants on a daily basis, you can hire us on a project basis, or you can enter an ongoing collaboration with us. In a separate blog post we’ve described just such a collaboration between Cresset, Isogenica and Biolauncher.

Computational chemistry consulting is seeing significant growth. The drivers behind this trend are the wish to outsource in-house computational chemistry to get maximum value for money, and the increasing recognition of the scientific value of computational chemistry expertise for discovery research. In the end though, it’s the results that count. Cresset’s consulting team has demonstrated the value of outsourcing by delivering valuable results for many clients, proven in terms of patented scientific discoveries that have led to solid business returns.

If you would like more information about doing business and science with Cresset consultants, please contact us.

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Dr Martin Slater,
Director of Consulting Services

 

Great Communication Makes a Great Consulting Project

In this series of blogs, Dr Martin Slater, Director of Consulting Services at Cresset, talks about what makes a great consulting project.

In the best discovery pipelines, computational chemists work closely with medicinal chemists to help direct and refine lead generation and optimization.  Making this work in an outsourcing model is a continual challenge for all parties.

It’s fair to say that good communication can make or break almost any scientific project, but it is particularly important when working in a consulting model.  We inevitably work in different locations to our clients, often across time zones, and of course we come across many different corporate cultures.

How closely we work with our clients depends absolutely on the individual client.  A few customers prefer a hands-off approach; they give us the input and we give them the results.  Provided the project has been well defined and expectations set accordingly, that can work well.  But the real strength comes from a more collaborative model.  Ideally, there will be a constant stream of information between the consultants and the client.

For example, a few years ago Cresset developed an extremely close working relationship with a US biotech firm.  We would speak on the phone several times a week to discuss the results we were getting.  Our initial collaboration was a hit finding project.  They developed the hits as we reported them.  We became an integral part of their team, giving their chemists our view of each compound from a computational point of view and discussing different ways to optimize them.

Success led to further projects and more extensive collaborations.  In the end, they bought our software and built their own in-house computational chemistry team.  Our work with them resulted in a patent, and eventually they were acquired by a major US corporation.

I mentioned already how important it is to define a project clearly and to set realistic expectations of success.  Making sure everyone understands the deliverables of a project, the methods we plan to use to get there, and the time frame makes communication during the project much easier.  Getting these process-oriented aspects defined clearly also means that administrative issues do not get in the way of the science.

Finally, it is important that we let our clients know from the start how likely we are to succeed in a project.  At the end of the day, we can define deliverables, but we can never guarantee what the results will be.  After all, we are engaged in scientific research for our clients.  But, I am pleased to say that we have many successes, and many satisfied customers who have come back to us again and again.

In my final post on consulting I’ll discuss some of the business models we use for consulting projects.

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Dr Martin Slater,
Director of Consulting Services

 

The Changing Face of Computational Chemistry

Chemistry software for drug discovery is becoming increasingly polarised into expert tools for computational chemists and 3D desktop modelling tools to support the work of medicinal chemists.

Day to day desktop tools enhance the work flow of medicinal chemists, while companies are increasingly choosing to outsource computational chemistry to consultants as a cost effective way of accessing expertise in a timely fashion.

Read the full article by Dr Martin Slater, Cresset’s Director of Consulting, on Page 38 of the Feb/Mar 2013 issue of Scientific Computing World.

The Advantages of Outsourcing Computational Chemistry

According to Martin Slater, Director of Consulting at Cresset Biomolecular Discovery, there are two main factors driving the current increasing trend to outsource computational chemistry: first, a trend to outsource across the discovery spectrum.  “The increasing fragmentation of the drug discovery business has brought an increase in companies that can move quickly to offer tailored research, often through the use of on demand services from consultants”. The second factor is that big pharma are seeking to reduce their R&D costs as many key patents are due to expire over the coming years.

This article appears in the January/February 2013 edition of sp2 Inter-Active magazine: The Advantages of Outsourcing Computational Chemistry (Part 2).

The first part of this article, The Advantages of Outsourcing Computational Chemistry (Part 1), appeared in the November/December 2012 issue of sp2 Inter-Active.

Great Science Makes a Great Consulting Project

Previously I’ve discussed the trend to outsource computational chemistry and great people. In this third post I talk about great science being one of the key factors to a great consulting project.

Cresset consultants always use the best software for the job at hand and we do not restrict ourselves to using only Cresset’s software. Having said that, clients often come to us for consultancy projects because of the innovative software we offer, underpinned by proven scientific methods.

What makes Cresset’s scientific software offering unique is field technology, a patented set of algorithms that describes molecules based on their biological activity. The resulting field point descriptors of molecules give a powerful basis for analyzing and comparing molecules using biological activity rather than chemical similarity (see Figure 1, below).

2D structures of structurally diverse bioisosteres both active at PDE3, cAMP (the natural substrate) and SKF93741. The field patterns of the compounds reveal that they are biologically similar.

fields_example
Figure 1: Closing the gap between chemistry and biology: two structurally diverse molecules with similar biological activity.
Above left: 2D structures of structurally diverse bioisosteres both active at PDE3, cAMP (the natural substrate) and SKF93741, a PDE3 inhibitor.
Above right: The field patterns of the compounds reveal that they are biologically identical and share the same activity.

Clients come to us with many different starting points for projects. Because Cresset’s technology can work with or without a structure of the target protein it can be used on the widest range of target classes. This also makes it easy to start a consulting project when the structure of the target protein is not known.

For example, you may have an active compound that is unusable due to off target activity or patent conflicts. Therefore, your goal is to modify this compound to avoid the undesirable effects while keeping the biology the same. We can characterize the molecule according to its field activity then look for compounds with new chemistry that have the same activity – often from a different structural class.

A client may wish to find an inhibitor for a natural substrate or peptide. Our team will use our software to mimic the chemical properties of the recognition sequence in order to find a small molecule inhibitor. We’ve also worked on projects where the starting point has been anti-bodies or large protein-protein interactions, but these are much harder to deal with computationally.

The case study Virtual Screening with 11βHSD-1 is an example of a virtual screening project Cresset worked on, that demonstrates the validity of Cresset’s field based approach.

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Dr Martin Slater,
Director of Consulting Services

Cresset Consulting – What Makes a Great Consulting Project?

In this series of blogs, Dr Martin Slater, Director of Consulting Services, talks about what ingredients contribute to the success of a consulting project.

There are three key ingredients vital to the success of a consulting project. First and foremost is the expertise of the consulting team. Second is the quality of the software and the reliability of the science used to deliver the results. Third, and the one variable that changes with each project, the success of a collaboration can hinge on the quality of communication between the customer and the team.

Great People Make a Great Consulting Project

Perhaps it sounds surprising, but I would always put the expertise of the consulting team before the software. Of course, they are both important, and you cannot perform computational chemistry without proven scientific computational methods. But we are talking about scientific research, and it takes excellent scientists to deliver excellent science.

We don’t carry out research by putting a postgraduate in front of a screen so they can input data then tell customers what the software tells them. What Cresset offer our customers is years of combined scientific expertise from a world class computational chemistry team.

Our customers are typically small to medium size companies who do not have the resources to build a dedicated in-house computational chemistry team. They could perhaps choose to hire one computational chemist to work with their medicinal chemists, but this could really limit the breadth of the computational chemistry they can deploy.

Our team of scientists have experience in structural biology, medicinal chemistry, computational chemistry and cheminformatics. Together they have over 100 years of combined industry experience on a very wide range of biological targets and therapeutic areas. In fact, because of our range of consulting projects and industry backgrounds, our team typically has much greater experience than most in-house pharmaceutical computational chemistry teams.

We work on projects from scaffold hopping and ligand based virtual screening, fragment replacement, fragment growth and SAR analysis including 3D QSAR using fields. The following diagram shows the wide range of fields in which Cresset consultants have worked.

And this experience matters. Computational chemistry is not magic, it is science. Scientific tools need scientists to provide intelligent input and interpret the results. It is Cresset’s expertise and depth of experience that really deliver results for our customers.

Cresset's Consultancy Fields
Figure 1: The wide range of fields in which Cresset consultants have worked

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Dr Martin Slater,
Director of Consulting Services