Vicent Rodeschini, Hugues Lemoine & Didier Roche
Despite the re-emergence of combinatorial approaches to explore considerably larger chemical spaces, notably with DNA encoded libraries1 (DEL) and affinity selection-mass spectrometry2 (AS-MS), compound collections used for Hit-identification tackle a very small proportion of the 1060 estimated size of the drug-like chemical space.3 Just looking at the diversity of drugs entering the clinic each year, one can easily understand that this diversity can hardly be matched with synthetic compound collections. New possibilities are offered today with generative machine learning4 or the use of non-enumerated massive combinatorial chemical spaces5 to bias compound design when structural information is available.
Since its inception 18 years ago, Edelris has designed and explored a diverse and biorelevant area of the chemical space, the Keymical SpaceTM, comprising innovative synthetic NP-like, sp3-rich topologies.6
In our hand, this unbiased tangible chemical space has proved to be very successful for the rational design of innovative target modulators. We will share in this presentation our success stories as well as the limitations encountered in applying virtual screening towards hit identification.
1. Kunig, V., Potowski, M., Gohla, A. & Brunschweiger, A. DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences. Biol. Chem. 399, 691–710 (2018).
2. Prudent, R., Annis, D. A., Dandliker, P. J., Ortholand, J.-Y. & Roche, D. Exploring new targets and chemical space with affinity selection-mass spectrometry. Nat. Rev. Chem. 5, 62–71 (2020).
3. Reymond, J.L. The Chemical Space Project. Acc. Chem. Res. 48, 3, 722–730 (2015).
4. Meyers, J., Fabian, B. & Brown, N. De novo molecular design and generative models. Drug Discov. Today 26, 2707–2715 (2021).
5. Hoffmann, T. & Gastreich, M. The next level in chemical space navigation: going far beyond enumerable compound libraries. Drug Discov. Today 24, 1148–1156 (2019).
6. Nelson, A. & Roche, D. Innovative approaches to the design and synthesis of small molecule libraries. Bioorg. Med. Chem. 23, 2613 (2015).