Ray Boffey¹, Chris Richardson¹, Duncan Hannah¹, Marc Rogers², Robert Kirby², Ian Witton², Trevor Perrior¹

1. Domainex Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, CB10 1XL
2. Metrion Biosciences Ltd, Riverside 3; Suite 1, Granta Park, Cambridge, CB21 6AD, United Kingdom

• Domainex and Metrion Biosciences have formed an alliance to identify new chemical hits against ion-channel targets. Key to this collaboration are Domainex’s experience in hit identification and Metrion Bioscience’s expertise in ion channel screening and pharmacology.
• The transient receptor potential cation channel A1 (TRPA1) is a voltage-dependent non-selective cation channel. It is an established therapeutic target, antagonists of which may have utility in the treatment of pain and the management of chronic cough. Bautista et al¹ described TRPA1 as a “gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract”.
• As part of this alliance, Domainex applied its proprietary LeadBuilder platform to identify commercial compounds for screening based on Metrion’s validated agonist and antagonist profiles of reference compounds. Compounds were then purchased and screened at Metrion Biosciences through a cascade of assays, to identify true antagonists of TRPA1.

• 400 compounds were purchased and assayed against human TRPA1 at 10 µM in a validated Ca²⁺ imaging assay able to detect agonists and antagonists.
• 14 hits were progressed to IC₅₀ determination, revealing 3 novel antagonists.
• The AMG-0902 derived pharmacophores produced the majority of the hit compounds with the HC-030031 and toxin derived pharmacophores also producing antagonist hits.
• The hits were a balance between compounds closely related to one or more query molecules, such as the match illustrated, and more diverse compounds.

• Domainex has applied its LeadBuilder platform to the identification of antagonists for the therapeutically relevant ion channel TRPA1.
• The ligand-based study used NMR derived structural data and site-directed mutagenesis data as well as small molecule SAR.
• Small molecule hits have been obtained from multiple chemotypes with micromolar potency. These include compounds with high similarity to the query molecules and also some more diverse structures. The compound structures are suitable for optimisation as part of a drug discovery project.
• Metrion Biosciences offers expertise in detailed pharmacologic evaluation of ligands and this was used to underpin the ligand selection used for the virtual screen.

1. Bautista et al, Ann Rev Physiol, 75, 181, (2013);
2. Paulsen et al, Nature, 520, 511, (2015);
3. Chen and Hackos, Naunyn Schmiedebergs Arch Pharmacol, 388(4), 451, 2015);
4. Lehto et al, Mol Pain, 12, (2016),PMID:27899696;
5. Rooney et al, J Med Chem, 57(12), 5129, (2014);
6. Gui et al, Curr Biol, 24, 473, (2014);
7. ChEMBL24: www.ebi.ac.uk/chembl;
8. Schenkel et al, J Med Chem, 59(6), 2794, (2016)