Navigating a 1E+60 Chemical Space

Herein we report a virtual library of 1E+60 members, a common estimate for the total size of the drug-like chemical space. The library is obtained from 100 commercially available peptide and peptoid building blocks assembled into linear or cyclic oligomers of up to 30 units, forming molecules within the size range of peptide drugs and accessible by solid-phase synthesis. We demonstrate ligand-based virtual screening (LBVS) using the peptide design genetic algorithm (PDGA), which evolves a population of 50 members to resemble a given target molecule using molecular fingerprint similarity as fitness function. Target molecules are reached in less than 10,000 generations. Like in many journeys, the value of the chemical space journey using PDGA lies not in reaching the target but in the journey itself, here by encountering molecules otherwise difficult to design. We also show that PDGA can be used to generate median molecules and analogs of non-peptide target molecules.