Making molecules with light to improve the chance of drug discovery success

Brian Cox, Professor of Pharmaceutical Chemistry at the University of Sussex, has brought his skills and knowledge gained over 30 years within the pharmaceutical industry, to set up a start-up company and to carry out ground breaking research producing photochemically derived molecules which could improve the success rates in drug discovery and help tackle neglected diseases.

“The molecules you can access through photochemistry can occupy a very different part of chemical space. It’s like access to a hidden garden,” said Brian Cox, Professor of Pharmaceutical Chemistry at the University of Sussex while gesturing at an image of a garden wall with sunlight pouring through an arched doorway in the middle. “On this side of the gate you’ve got all the conventional chemistry, which is producing molecules that are in everybody’s archives. But you walk through that gate – where you’ve got photochemistry – and there’s a whole universe of untapped molecules, billions of new molecules, to be made.”

Pharmaceutical companies use libraries of molecules, ranging from natural products to molecules made in labs, to carry out experiments. Called assays, these experiments seek to find out whether a molecule modifies the activity of a biochemical “target”, such as an enzyme or a receptor, to either block or sometimes enhance the biochemical process. “Companies have millions and millions of molecules in store, either in solution or solid. If they identify a biochemical target that they believe is important in a disease, they will set up an assay and screen literally their whole archive of compounds against it,” said Cox. “They might have millions of compounds, but many companies have historically made and purchased the same cluster of boring compounds.”

Cox has first-hand experience of the drug discovery process from start to finish gained during his 30 years within the pharmaceutical industry. Having suffered with asthma as a child, he became fascinated by how medicines worked, and interested in drug discovery. In his role as the Head of Chemistry in the UK at Novartis, and previously at GSK, Cox oversaw the development of a number of compounds for the treatment of respiratory diseases, most notably fevipiprant for treating asthma.

Novartis, like all companies, bought molecules from catalogues, “We worked on one set of molecules for many months. We were just in a position to patent it, when three patents from other companies arrived with exactly the same molecules, against exactly the same target! There are many examples of this,” said Cox. “Drug development is tough enough as it is without everyone playing in the same very small molecular space.” 

Making unique molecules using photochemistry

Novartis, like many companies, pledged to buy bespoke molecules going forward to expand the molecular “playing field”. Cox and a long term collaborator Professor Kevin Booker-Milburn from the University of Bristol spotted a gap that they could fill and set up a start-up company, Photodiversity Ltd, in 2015. “That’s the basis of Photodiversity Ltd. To make molecules that are really unique and occupy chemical space that other chemistries don’t provide. And people are really interested in it.”  That’s what they have been doing ever since.  

Photodiversity Ltd aims to accelerate industry efforts to develop new products by designing and synthesising complex small-molecule compound libraries using photochemistry, chemistry that is induced by light, or photons, and automated synthesis methods. “You literally shine light on molecules and they undergo a chemical transformation to create something new.” Photochemistry enables chemical transformations that are very hard to achieve with ‘ground state chemistry’, which is the lowest energy state or the most stable configuration of an atom, molecule, or ion. “With photochemistry, molecules are moved to an excited state where they can undergo some really quite bizarre transformations – reactions that would require immense amounts of energy to achieve with ground state chemistry,” said Cox. “Very often photochemistry produces molecules with greater three dimensionality with unusual vectors.”

It has been shown that molecules with enhanced three-dimensionalality, like those created through photochemistry and automated chemistry techniques, are more likely to help a molecule bind to chemical targets, providing a starting point for a successful drug discovery programme. Given the pressures within research and development teams in the pharmaceutical industry to deliver new medicines and patents, this is critical. “Patents are all about novelty,” said Cox. “You’ve got something that no one else has.”

Photodiversity Ltd has already had significant successes working with a number of pharmaceutical clients, including providing novel libraries of molecules to Bayer, Merck and AbbVie, and have recently published a paper with AbbVie on the design, synthesis, and computational structural analysis of a series 3D compounds. Photodiversity Ltd is creating molecular scaffolds for companies, like Polyphor and Bicycle Therapeutics and has sold its scaffolds to university drug discovery groups, such as QEDDI at the University of Queensland.

Creating novel molecules to treat neglected diseases 

Cox moved to the University of Sussex in 2012, bringing his techniques honed in the pharmaceutical industry to the university. His lab has focussed on developing molecules that could treat neglected diseases, the name given to communicable diseases that affect more than one billion people and cost developing economies billions of dollars every year.

Researchers within his lab are working on solutions to treat Chagas disease, which is caused by parasites transmitted by the blood-sucking triatomine bug, which bites unsuspecting humans while they sleep and can eventually result in heart failure and cardiac arrest. Through collaboration with the University of Geneva and the Drugs for Neglected Diseases Institute, the lab is making analogues, a compound that has a similar structure to a natural product, which has been shown to be active against the parasite carried by the bug. If successful in finding a new drug, the collaboration could eventually change the lives of the 6 – 7 million people living with the Chagas disease, mostly in Latin America. 

Photodiversity Ltd is also looking at developing molecules that could someday impact on malaria, which, according to the World Health Organization, leads to an estimated 228 million cases worldwide each year, with 405,000 malaria deaths in 2018 alone. “It’s a tough organism to crack”, says Cox, referring to the Plasmodium parasites (mainly Plasmodium falciparum and Plasmodium vivax) that are transmitted by the bite of mosquitoes. “The major issue is the constant development of resistance to the current drugs, so you’re always behind the curve. All the research is underpinned by the need to find novel molecules to kill the parasite.”

Photodiversity Ltd has provided Medicines for Malaria Venture, a non-profit organisation which aims to reduce the burden of malaria in disease-endemic countries by developing new, antimalarial drugs, with three libraries of novel molecules to screen. One library has already provided molecules which look promising. “The number of times you get hits are not great compared to other organisms. But one of our libraries had a large number of molecules – a cluster of hits, or a real sweet spot,” said Cox. It’s been a very successful relationship and they are already planning to produce more libraries for the organisation.

Clearly the potential of these new molecules is what drives Cox forward with his research. “It is literally about creating something that has never been made before, and seeing what biological effect it can have. That has always been an amazing thing for me, as a synthetic chemist. When you have made something in the lab, and think: this has probably never existed before. And then to see that molecule be screened against malaria and be active – it gives you a real buzz!” 

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