Spinout Equinox Pharma speeds up and reduces the cost of drug discovery pinout Equinox Pharma1 provides a service to the pharma and biopharma industries that helps in the development of new drugs. The company, established by researchers from Imperial College London in IMPACT SUMMARY 2008, is using its own proprietary software to help speed up and reduce the cost of discovery processes. S Spinout Equinox Pharma provides services to the agri- tech and pharmaceuticals industries to accelerate the Equinox is based on BBSRC-funded collaborative research The technology also has applications in the agrochemical discovery of molecules that could form the basis of new conducted by Professors Stephen Muggleton2, Royal sector, and is being used by global agri-tech company products such as drugs or herbicides. Academy Chair in Machine Learning, Mike Sternberg3, Chair Syngenta. The company arose from BBSRC bioinformatics and of Structural Bioinformatics, and Paul Freemont4, Chair of structural biology research at Imperial College London. Protein Crystallography, at Imperial College London. “The power of a logic-based approach is that it can Technology commercialisation company NetScientific propose chemically-novel molecules that can have Ltd has invested £250K in Equinox. The technology developed by the company takes a logic- enhanced properties and are able to be the subject of novel Equinox customers include major pharmaceutical based approach to discover novel drugs, using computers to ‘composition of matter’ patents,” says Muggleton. companies such as Japanese pharmaceutical company learn from a set of biologically-active molecules. It combines Astellas and agro chemical companies such as knowledge about traditional drug discovery methods and Proving the technology Syngenta, as well as SMEs based in the UK, Europe, computer-based analyses, and focuses on the key stages in A three-year BBSRC grant in 2003 funded the work of Japan and the USA. drug discovery of target identification, lead validation, and Muggleton and Sternberg in their initial development of the The company is also using their software in-house, to lead optimisation. technology. BBSRC follow-on funding was also provided in develop new antibiotics. 2006 for a further year. The software can screen tens of millions of potential molecules in only a few hours, and is more accurate than BBSRC support enabled Dr Ata Amini, a researcher at company’s proprietary software for drug discovery. This was other software-based approaches to identifying promising Imperial College London, to prove the technology and for called INDDex (Investigational Novel Drug Discovery by leads for drug discovery. details to be published5. The researchers developed a unique Example)8. machine learning method known as SVILP (Support Vector Inductive Logic Programming) and filed patents for it. These More recently, further development work has been were granted in Japan and USA and remain pending in undertaken by chemoinformatics PhD student Chris Europe6. Reynolds. His work, supported by a BBSRC CASE studentship between Equinox and Imperial College London, involves Imperial Innovations, part of the university, and technology integrating chemical synthesis into in silico (performed by commercialisation company NetScientific Ltd subsequently computer simulation) ‘hit’ discovery of drugs. both made investments of £250,000 in Equinox to in-license (an agreement to collaborate between companies with Logic-based drug discovery different strengths) drug discovery technology and develop In recent years, computer-based virtual screening has the business7. become an integral part of the drug discovery process. As part of this development, the INDDEx software uses its Scientists examine a computer model of a biologically-active Dr Amini was subsequently employed by Equinox, where molecular structure. logic-based rules to search databases of millions of small he used the concepts of the technology to develop the molecules for those that could potentially form the basis of 1 Spinout Equinox Pharma speeds up and reduces the cost of drug discovery new drugs. In addition, the software can perform ‘scaffold 50% prediction rate hopping’ – a process that enables novel compounds to be Existing high-throughput conventional screening is REFERENCES 1 Equinox Pharma Limited found while maintaining the known activity of an original expensive and limited to a few compounds at a time. 2 Professor Stephen Muggleton: http://www.imperial.ac.uk/people/s. substance. By identifying novel molecular structures that Computer-based virtual screening does not have these muggleton have little similarity to the original substances, the software limitations, but not all in silico approaches are as effective 3 Professor Michael Sternberg: http://www.imperial.ac.uk/people/m.sternberg increases the chance of discovering patentable molecules. as the one developed by Equinox. Some only achieve a 4 Professor Paul Freemont: http://www.imperial.ac.uk/people/p.freemont 5 Amini, A., Muggleton, S. H., Lodhi, H. & Sternberg, M. J. (2007). A novel INDDEx uses artificial intelligence to create rules that 15% (or lower) hit rate, whereas INDDEx is able to achieve logic-based approach for quantitative toxicology prediction. J Chem Inf identify the chemical properties of molecules which are up to a 50% prediction rate. In view of this substantial Model 47, 998-1006. 6 Patent: Muggleton, S.H., Lodhi, H. M., Sternberg, M.J.E. & Amini, A. (2006) responsible for drug activity. In-house information, and advantage, INDDEx can screen large numbers of Support Vector Inductive Logic Programming –PCT /GB2006/003320/ information provided by clients, act as ‘training’ datasets compounds rapidly and cost effectively. In some instances, Granted USA and Japan, Pending in EU. 7 Imperial Innovations: Investment in Equinox Pharma of substances that have already been screened against up to 40 million compounds have been screened by Equinox a target molecule. From the training dataset, INDDEx in a matter of hours – with important implications for 8 Reynolds, C. R., Amini, A. C., Muggleton, S. H. & Sternberg, M. J. E. (2012). generates a set of logic-based rules about the relative speeding up drug discovery. Assessment of a Rule-Based Virtual Screening Technology (INDDEx) on a position of parts of a molecule that display desirable Benchmark Data Set. Journal of Physical Chemistry B 116, 6732-6739. 9 Di Fruscia, P., Zacharioudakis, E., Liu, C., Moniot, S., Laohasinnarong, S., characteristics. Equinox is following a mixed-business model of ‘fee-for- Khongkow, M., Harrison, I. F., Koltsida, K., Reynolds, C. R., Schmidtkunz, K., service’ and in-house drug discovery. Currently, Equinox Jung, M., Chapman, K. L., Steegborn, C., Dexter, D. T., Sternberg, M. J. E., Lam, E. W. F. & Fuchter, M. J. (2015). The Discovery of a Highly Selective On completion of screening and searches of small molecules is applying its technology to develop novel antibiotics. In 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 by the software, medicinal chemists are presented with rules addition, INDDEx has been used at Imperial College London Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model. ChemMedChem 10, 69-82. and promising lead molecules, which can then be tested to progress the development of inhibitors of SIRT2 – a 10 Syngenta: http://www3.syngenta.com/country/uk/en/about/businesses/ in the laboratory. The results are in a form that is readily potential target for the treatment of Parkinson’s disease9. Pages/Our_UK_businesses.aspx understood, helping direct the next step of drug discovery. Customers for the services provided by Equinox include “It’s incredibly exciting to transfer the results of academic major international pharmaceutical and agrochemical research into a company and have a commercial framework companies and SMEs based in the UK, Europe, Japan to apply the approach to drug discovery,” says Professor and the USA. One of its customers at Syngenta10, an Sternberg. “We’ve proved the technology with commercial agrochemical company with 29,000 employees in over and academic partners and our next project will be to apply 90 countries, says, ‘We were impressed with the ability of INDDEx to search for novel antibiotics, which will address INDDEx to produce good structure-activity relationship one of the global challenges in healthcare.” models for activity and selectivity in a series with very difficult molecules to analyse.’ 2.