ZINC-22─A Free Multi-Billion-Scale Database of Tangible Compounds for Ligand Discovery.

Purchasable chemical space has grown rapidly into the tens of billions of molecules, providing unprecedented opportunities for ligand discovery but straining the tools that might exploit these molecules at scale. We have therefore developed ZINC-22, a database of commercially accessible small molecules derived from multi-billion-scale make-on-demand libraries. The new database and tools enable analog searching in this vast new space via a facile GUI, CartBlanche, drawing on similarity methods that scale sublinearly in the number of molecules. The new library also uses data organization methods, enabling rapid lookup of molecules and their physical properties, including conformations, partial atomic charges, c Log P values, and solvation energies, all crucial for molecule docking, which had become slow with older database organizations in previous versions of ZINC. As the libraries have continued to grow, we have been interested in finding whether molecular diversity has suffered, for instance, because certain scaffolds have come to dominate via easy analoging. This has not occurred thus far, and chemical diversity continues to grow with database size, with a log increase in Bemis-Murcko scaffolds for every two-log unit increase in database size. Most new scaffolds come from compounds with the highest heavy atom count. Finally, we consider the implications for databases like ZINC as the libraries grow toward and beyond the trillion-molecule range. ZINC is freely available to everyone and may be accessed at cartblanche22.docking.org, via Globus, and in the Amazon AWS and Oracle OCI clouds.

ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery.

Identifying and purchasing new small molecules to test in biological assays are enabling for ligand discovery, but as purchasable chemical space continues to grow into the tens of billions based on inexpensive make-on-demand compounds, simply searching this space becomes a major challenge. We have therefore developed ZINC20, a new version of ZINC with two major new features: billions of new molecules and new methods to search them. As a fully enumerated database, ZINC can be searched precisely using explicit atomic-level graph-based methods, such as SmallWorld for similarity and Arthor for pattern and substructure search, as well as 3D methods such as docking. Analysis of the new make-on-demand compound sets by these and related tools reveals startling features. For instance, over 97% of the core Bemis-Murcko scaffolds in make-on-demand libraries are unavailable from "in-stock" collections. Correspondingly, the number of new Bemis-Murcko scaffolds is rising almost as a linear fraction of the elaborated molecules. Thus, an 88-fold increase in the number of molecules in the make-on-demand versus the in-stock sets is built upon a 16-fold increase in the number of Bemis-Murcko scaffolds. The make-on-demand library is also more structurally diverse than physical libraries, with a massive increase in disc- and sphere-like shaped molecules. The new system is freely available at zinc20.docking.org.