Chemical Space from First Principles

Designing new drugs molecules is both fun and critically important for addressing unmet medical needs. While novelty is readily available but very difficult to access in large and structurally complex molecules such as natural products, our aim is to identify novel but simple and easily synthesizable molecules by enumerating chemical space from first principles and comparing its contents with known molecules.^1–4 I will discuss recent examples from our group spanning from enumeration to virtual screening, synthesis and identification of novel bioactive small molecules and peptides.^5,6

(1)         Ruddigkeit, L.; van Deursen, R.; Blum, L. C.; Reymond, J. L. Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17. J. Chem. Inf. Model. 2012, 52 (11), 2864–2875. https://doi.org/10.1021/ci300415d.
(2)         Buehler, Y.; Reymond, J.-L. Expanding Bioactive Fragment Space with the Generated Database GDB-13s. J. Chem. Inf. Model. 2023, 63 (20), 6239–6248. https://doi.org/10.1021/acs.jcim.3c01096.
(3)         Orsi, M.; Probst, D.; Schwaller, P.; Reymond, J.-L. Alchemical Analysis of FDA Approved Drugs. Digital Discov. 2023, 2 (5), 1289–1296. https://doi.org/10.1039/D3DD00039G.
(4)         Orsi, M.; Reymond, J.-L. Navigating a 1E+60 Chemical Space of Peptide/Peptoid Oligomers. Mol. Inf. 2024, e202400186. https://doi.org/10.1002/minf.202400186.
(5)         Bonvin, E.; Orsi, M.; Paschoud, T.; Gopalasingam, A.; Reusser, J.; Köhler, T.; van Delden, C.; Reymond, J.-L. Antimicrobial Peptide-Peptoid Macrocycles from the Polymyxin B2 Chemical Space. Angew. Chem., Int. Ed. Engl. 2025, e202501299. https://doi.org/10.1002/anie.202501299.
(6)         Carrel, A.; Yiannakas, A.; Roukens, J.-J.; Reynoso-Moreno, I.; Orsi, M.; Thakkar, A.; Arus-Pous, J.; Pellegata, D.; Gertsch, J.; Reymond, J.-L. Exploring Simple Drug Scaffolds from the Generated Database Chemical Space Reveals a Chiral Bicyclic Azepane with Potent Neuropharmacology. J. Med. Chem. 2025. https://doi.org/10.1021/acs.jmedchem.4c02549.