Biomedical research experts are calling for better use of chemical probes to improve our understanding of protein function and the foundations upon which much of modern drug discovery and development rests.
In a maintenance in Nature CommunicationProfessor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at the Institute of Cancer Research in London, and Professor Cheryl ArrowsmithChief Scientist for the Structural Genomics Consortium (SGC) Toronto Laboratories and Professor of Medical Biophysics at University of Torontoexpose the main problems associated with the use of chemical probes in biomedical research and highlight new projects aimed at increasing the number and quality of chemical tools available to researchers.
Chemical probes are small molecules used to test the activity of a protein in a cell, often by inhibiting it.
Expert advice on chemical probes
One of the projects discussed is a new and improved version of an easy-to-use online resource for chemical probes. The portal of chemical probesrelaunched in 2021, relies on the expertise of an international community of 200 researchers in chemical biology, chemistry and pharmacology, and relies on the analysis of big data.
The portal aims to solve a central problem in biomedical research by encouraging the use in laboratory experiments of better and better chosen chemical probes – the molecular tools, usually protein inhibitors, which facilitate the understanding of biological processes and that are important to support the conclusions of the research.
A probe for each protein
Goal 2035 is a community-based research initiative aimed at accelerating the development of a chemical probe for every protein in the human proteome by 2035. Led by the SGC, Target 2035 brings together scientists from various fields of drug discovery, including biochemists, structural biologists, medicinal chemists, testing scientists and computer scientists. chemists.
With a focus on open and collaborative science and new technologies, Target 2035 aims to accelerate the development of new, high-quality chemical probes for the 90% of human proteins that have yet to be studied for the potential discovery of medications.
Powerful tools for biomedical research
Chemical probes are powerful tools routinely used to uncover how individual proteins are involved in health and disease, including in cancer, dementia and recently Covid-19, and ultimately lead to the discovery of new drugs.
But the quality of these reagents varies widely, and the use of suboptimal tools in research is widespread. Using poor or poorly selected compounds as tools can produce misleading results.
Better use of chemical probes could also save the biomedical research sector billions of pounds, by ensuring that new disease therapies are developed from a better and more robust understanding of their biological effects, and are therefore less likely to fail in expensive clinical trials.
Quickly provide expert information
Developed by ICR scientists with support from organizations including the SGC, Welcome and Cancer research in the UKThe new Chemical Probe Portal aims to encourage the widespread selection and use of the most appropriate high-quality chemical probes, particularly within the academic biology community.
One of the major updates from the previous iteration of the portal is a new process for sifting through massive datasets, recommending compounds of interest to consider as probes for further analysis by experts.
Researchers from academia and industry can also submit promising tools to the portal, which will be reviewed by an expanded panel of nearly 200 experts before the information is released free of charge to researchers around the world.
Expand and improve data
Other major portal updates include information and expert advice on hundreds of new chemical tools.
They include inhibitors of proteins previously considered largely non-drug-like, such as KRAS, agonists of cell surface receptor molecules, GPCRs, including the serotonin receptor HTR2A, as well as new chemical tools such as PROTACs and molecular glues – dual function molecules that guide proteins to the cellular degradation system to be broken down.
In the past year alone, the number of probes listed on the portal has increased by 60% to 520. Hundreds of new protein targets have been added, increasing the variety of tools researchers can use and expanding the impact in different research fields, including neurology and immunology.
Data sources include KPIs canSARthe world’s largest public cancer drug discovery resource, and probe minera leading community resource for evaluating chemical probes based on large-scale medicinal chemistry data.
The AI-enabled canSAR contains data on 500,000 protein structures and three million surface cavities of nearly 110,000 macromolecules, all of which are annotated and organized so that machine learning algorithms can easily analyze the data , as well as clinical and other data.
Probe Miner has evaluated over 1.8 million small molecules for their potential to act as chemical probes against 2,200 human protein targets.
Laying a solid foundation for research
Dr. Albert Antolin, ICR Fellow and Junior Team Leader at ICR, and one of the principal investigators of the Chemical Probe Portal, said: “The Chemical Probe Portal contains a host of new updates. day, including detailed information on hundreds of new molecules, a more effective use of big data and, above all, renewed support from hundreds of leading international experts in the best use of chemical probes in research.
“The portal provides all the key information to facilitate the selection of chemical probes in an easy to use way. It helps guide the use of chemical probes in thousands of experiments, laying a stronger foundation for basic research and drug discovery in a wide range of diseases, including cancer.
Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at ICR and Executive Director of the Chemical Probes Portal, said:
“The incorrect selection and use of chemical probes is widespread in biomedical research and, unfortunately, leads to misleading or erroneous conclusions being drawn from the results of experiments. In extreme cases, this can derail drug discovery and clinical trials and result in the unnecessary waste of hundreds of millions of pounds of research funding.
“With the Chemical Probe Portal and its close interaction with the Target 2035 initiative, our goal is to give the research community an accessible resource, backed by the best data and world-renowned experts in using the best chemical probes for the study of particular proteins New developments on the portal will now further improve the selection and use of the best available tools for experimental research and thus increase the quality and robustness of biomedical research.