ZINC 15--Ligand Discovery for Everyone

Abstract

Many questions about the biological activity and availability of small molecules remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation, purchasability, target, and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compounds--effectively all organic molecules that are for sale--a quarter of which are available for immediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites, drugs, natural products, and annotated compounds from the literature. Compounds may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new analysis tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots--all molecules are available in biologically relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.

Figure 1

The ZINC15 Web interface. A: Selected ZINC substance subsets showing the number of purchasable bioactive and biogenic subsets. The navigation bar (1) provides access to other resources. Click on the subset name (2) to browse or download a subset. (3) Estimates of the number of each subset. (4) Inset of dropdown menu providing access to other resources. B: Endogenous human metabolites subset page, represented as tiles. The page navigation tool (1), the Get total tool (2), the breadcrumbs (3), the selection tool (4), and the download tool (5). Click on any molecule’s number (6) to view its detail page. (7) Download popup (inset).

Figure 2

Chemical search in ZINC. A: Search using a single molecule. (1) The user may seed the drawing with chemical or drug names, ZINC IDs, InChI, InChIkey, or original catalog numbers. The search options may be edited prior to search (2), which is run using one of four buttons below drawing (3): exact match, substructure, and two kinds of similarity. B: Search using many molecules in a single operation. Specify one molecule per line in a file (4) or by pasting (5). Additional search options (6). Format of results may be specified (7, inset 8) prior to running the resolver. Buttons to browse subsets or view subsets (9) as well as general free text search.

Figure 3

ZINC reference information. A. ZINC results may be accessed in 11 formats plus the Web pages. Three line-oriented formats are easy to parse for both people and computers. Three machine readable formats provide for rich and flexible data interchange between programs. Five formats provide molecule structures for docking or modeling. Each format is also available compressed using a .gz suffix. B. Compounds are classified by how they may be purchased based on their current catalog membership. There are five primary levels and three derived levels. C. We classify substances into six levels by the most reactive group they possess, based on SMARTS patterns.D. 3D representations are associated progressively with the pH range at which they become relevant for docking.

Figure 4

Molecule detail page. A. Showing (1) ZINC ID, name if known, subset membership, (2) properties and 2D depiction, (3) 3D representations if available, (4) purchasing information, and (5) annotated catalog membership, (6) breadcrumbs indicating current location, (7) selection tool for refinement of query, and (8) download tool. B. Interesting bioactive and biogenic analogs section of molecule detail page: (1) similar biogenic compounds, (2) similar bioactive compounds, (3) compounds with a shared scaffold, (4) similar aggregators, and (5) similar purchasable compounds currently too slow to calculate. A find more button in each case will find more of the same.

Figure 5

Tranche browser for selection and download of chemical libraries. Physical-chemical space has been divided into 11 bins of polarity-hydrophobicity (calculated logP, vertical) (1) and size (molecular weight, horizontal) (2). Subsets of this space may be selected in 2D (SMILES) or 3D (Figure 3A) (3). Purchasability level (Figure 3B) (4) and reactivity (Figure 3C) (5) may also be specified. For 3D only, net molecular charge (6) and pH range (Figure 3D) (7) may also be specified. Presets (8) correspond to community practice (e.g., “lead-like”, “fragment-like”), and Download (9) provides for five methods to access the selected molecules.