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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• The chemical space for drug discovery is rapidly expanding with billions of make-on-demand compounds.
• Searching this vast chemical space for novel ligands presents a significant challenge.

Purpose of the Study:

• To introduce ZINC20, an updated version of the ZINC database.
• To incorporate billions of new molecules and novel search methodologies into ZINC20.
• To analyze the structural characteristics and diversity of make-on-demand compounds.

Main Methods:

• Development of ZINC20 with expanded molecular libraries.
• Implementation of graph-based search methods (SmallWorld, Arthor) and 3D docking.
• Analysis of Bemis-Murcko scaffolds and molecular shape diversity in make-on-demand sets.

Main Results:

• ZINC20 provides access to billions of new molecules, significantly increasing searchable chemical space.
• Over 97% of make-on-demand Bemis-Murcko scaffolds are novel compared to in-stock collections.
• Make-on-demand libraries exhibit greater structural diversity, including increased disc- and sphere-like molecules.

Conclusions:

• ZINC20 enhances ligand discovery by providing access to a vastly expanded and diverse chemical space.
• Make-on-demand compounds offer unique scaffolds and structural properties not found in traditional libraries.
• The ZINC20 database is freely available, facilitating broader research in drug discovery.