Impact case study database

Meeting the requirements of diverse users

The impact of software is generally dependent on both its power and its ease of use. Throughout the Phyre development cycle, we obtained extensive feedback from users about their specific needs and this directly drove the design of both the back-end algorithms and the web front-end. These mechanisms promoted extensive use by non-commercial users over many years and the reputation of Phyre led to its subsequent rapid and widespread uptake by commercial users.

Dissemination to non-academic users

In addition to academic publications, Phyre has been presented to both the academic and commercial communities at the tech track of the major bioinformatics meeting (ISMB) annually since 2015 and at over 12 UK training workshops including at Oxford and at the EBI [A]. Academic and commercial users can find out about Phyre via its listings on its own page on Wikipedia and sites listing bioinformatics software such as ELIXIR and ExPASy [B, C]. Additionally, we provide e-mail support. As a result of the quality of the algorithm, its user-friendly interface, its short turnaround time (typically a few hours for a single sequence) and our support, there have been a large number of academic publications reporting the use of Phyre. This has promoted Phyre to commercial users who consequently availed themselves of Phyre when it made available for their use.

Usage figures

In Phyre a user inputs a single protein sequence for analysis as this is recorded as a submission. Distinct users are based on a unique IP address. Over the period 1 Aug 2013 to 31 July 2020 there were over 500,000 distinct users who submitted over 1,000,000 jobs [D]. From 1 October 2018 to 31 July 2020 there were over 900 commercial users (as identified by clicking a radio button) and over 2,500 submitted jobs [D].

Commercial impact

Since October 2018 Phyre2 has been available to commercial users, mainly in the pharmaceutical and drug discovery sectors. Here we give five specific company examples where Phyre2 has become an integral part of their discovery pipelines and has positively impacted their development programmes and businesses.

Evotec is a leading international Contract Research Organisation specialising in discovery, optimisation and development of small molecule and anti-body based therapeutics for a wide variety of pharmaceutical organisations. Phyre2 is now used to aid in construct and solving structures by predominantly crystallography but also cryo-electron microscopy. Evotec states that “ It [Phyre2] has contributed to >40 projects over the past year with a focus on establishing appropriate protein constructs to support crystallography and also high-throughput and associated biochemical and biophysical assays.” Furthermore, this new approach has allowed them to “ identify dynamic loops and domain boundaries, which have been critical to the success of specific structural projects…” [E].

Hummingbird Bioscience is a biotechnology company founded in 2015 based in Singapore and the USA. They develop novel bio-therapeutics to revolutionize treatment outcomes using a unique antibody discovery platform combined with detailed insights from systems and computational biology. Hummingbird Bioscience’s Chief Technology Officer explains how Phyre2 is an integral part of their discovery platform. “ *We utilize Phyre2 on a regular basis to inform our Rational Antibody Discovery platform to help model protein structures which lack experimentally determined structures and to place known structures into context. These are critical steps to ensuring that our molecules achieve a desired mechanism of action when binding a target molecule. Without Phyre2 we would not have been able to do this.*” [F]. This company is relativity young and currently has two molecules entering Phase I trials. Both targeted at indication in oncology. Phyre2 has been critical is both of these projects, in particular, in the selection of the targets and epitopes. Hummingbird Bioscience states that “ *This would have been extremely difficult for the company at that early stage since commercially available tools were not financially viable at that stage. The fact that Phyre2 is freely available for commercial use was a crucial factor in the company’s success.*” [F]

Vernalis is a structure-based drug discovery company of some 70 employees, based near Cambridge, UK. Its main activity is using our integrated suite of biophysical, structural, and medicinal chemistry methods in collaboration with international pharmaceutical companies in the discovery and optimisation of small molecules as modulators of the function of proteins of therapeutic relevance. Most of our target proteins are selected by the collaborator, so our use of bioinformatics tools is mainly limited to construction of models where crystal structures are not available, and analysis of the likely variation in function across species or arising from mutations. One user at Vernalis Research, writes “ it is our general experience that many of the methods available online have varying and sometimes obscure interfaces and the results generated are difficult to interpret. For us, the main advantage that Phyre2 brings is the intuitive interface to a collection of leading edge, robust methods, and the way the results are analysed and presented. The main impact on our research is that we can perform such analyses which inform the early stages of drug discovery projects.” [G]

BASF is a multinational chemicals company with sales of €59 billion in 2019. Phyre has been used by the Belgium Innovation Centre, which has about 180 researchers and covers all aspects of the R&D process from the lab to the field. This Centre requires details of the 3D structure of proteins. A joint letter from the Site Director and Head of Intellectual Property states that “ Phyre has been successfully used in analysing a dozen proteins”. They describe the search algorithm as “ both accurate and efficient providing a turnaround time in a few hours which greatly facilitates our use in exploring hypotheses over the timescale required in our R&D pipeline” [H].

Domainex is a leading integrated drug discovery research service partner based near Cambridge, UK, offering tailored services, from expression of recombinant proteins, screening disease targets to identify hit compounds through to the discovery of pre-clinical drug candidates. The letter from a Principal Scientist at Domaniex states that “ Phyre is an extremely useful tool that quickly provides us with a large amount of target information. The structural prediction gives us information on potential domain boundaries, regions of disorder, potential ligand binding sites and the position of surface accessible lysine or cysteine residues that could be used for downstream labelling for assay development or biophysical analysis. The structural alignments provide us with direct links to related proteins that have already been successfully produced, providing us with established production methods.” [I]. In particular they have integrated Phyre into Combinatorial Domain Hunting (CDH) technology to identify physical domain boundaries.

Academic use that translates into commercial and societal impact

Determination of protein structure and its implication for functional assignment is central to a wide range of academic research in bioscience and biomedicine that then translates into commercial and societal impact. A search of Google Patents with “PHYRE AND PROTEIN” identified over 70 granted patents that cite Phyre [J]. These patents cover a wide range of application areas including: vaccine design (e.g. US-10495639-B2) by Virginia Commonwealth University, anti-cancer kinase inhibitors (US-9198891-B2) by New York University, HIV envelope immunogenic polypeptides (US-9855329-B2) by Los Alamos & Dana-Faber & Duke, and staphylococcal antigens (EP-2488547-B1) by University of Edinburgh.