ICR researchers use computational methods to find new bromodomain inhibitors, protein inhibiting chemicals that have an important role in cancer.
Scientists at The Institute of Cancer Research, London, have used computational methods to find new bromodomain inhibitors, a group of chemicals that inhibit proteins that have an important role in cancer.
Some bromodomain inhibitors are in early stage trials as treatments for cancer.
Using a specific sequence of computational models, including virtual docking of thousands of compounds into the crystal structures of bromodomains to predict how they bind to the protein, the scientists screened 2.4 million compounds and identified 143 potential bromodomain inhibitors.
Scientists at the Structural Genomics Consortium (SGC) in Oxford, one of the leading institutes in bromodomain research, tested these compounds in the lab and found that six of these compounds were indeed novel inhibitors of bromodomain 4 (Brd4). Moreover, they solved the crystal structure of 4 compounds bound to Brd4 and confirmed the computational predictions.
The study was published in the Journal of Medicinal Chemistry and was carried out by researchers in the Cancer Research UK Cancer Therapeutics Unit at the ICR, in collaboration with scientists from the Structural Genomics Consortium in Oxford. Work at the ICR was funded by Cancer Research UK with additional funding through the NIHR Biomedical Research Centre.
Bromodomains are protein domains that bind to nucleosomes, the principle storing unit of the human genome, and they also play an important role in controlling gene transcription. They carry out their functions by recognising epigenetic tags on target proteins. Bromodomains are vital for processes such as cellular growth and proliferation that are at the heart of diseases like cancer, so blocking their activity is a novel way to create new therapies for cancer and other diseases.
Scientists often face a challenge in identifying compounds for new drug discovery projects. Hit compounds are the starting points discovered at the beginning of the project which are then chemically modified until the final drug candidate has been reached. To identify these hit compounds drug discovery teams often rely on screening hundreds of thousands of chemicals, which is both expensive and time consuming.
To solve this problem, computational methods are increasingly used to screen millions of compounds in silico. While several examples have been described where this approach has been successful, limited understanding of how drugs interact with their targets and the high computational costs still make drug discovery a scientific challenge. This research shows that, by streamlining the approach, hit compounds for Bromodomains can be discovered more quickly and at a lower cost.
Dr Swen Hoelder, who led this work at the ICR, said: “In this study we show how computer simulation can be used to identify bromodomain inhibitors, an exciting and emerging class of epigenetic cancer targets.
“The ICR’s Cancer Therapeutics Unit has developed great expertise in computational screening, which is quickly becoming a viable option for drug discovery and helps to save time and resources. Together with our collaborators at the SGC we are now working on the discovery of other bromodomain inhibitors.”