DrugDomain 2.0: Comprehensive database of protein domains-ligands/drugs interactions across the whole Protein Data Bank

Abstract

Proteins carry out essential cellular functions - signaling, metabolism, transport - through the specific interaction of small molecules and drugs within their three-dimensional structural domains. Protein domains are conserved folding units that, when combined, drive evolutionary progress. The Evolutionary Classification Of protein Domains (ECOD) places domains into a hierarchy explicitly built around distant evolutionary relationships, enabling the detection of remote homologs across the proteomes. Yet no single resource has systematically mapped domain-ligand interactions at the structural level. To fill this gap, we introduce DrugDomain v2.0, an updated comprehensive resource, that extends earlier releases by linking evolutionary domain classifications (ECOD) to ligand binding events across the entire Protein Data Bank. We also leverage AI-driven predictions from AlphaFold to extend domain-ligand annotations to human drug targets lacking experimental structures. DrugDomain v2.0 catalogs interactions with over 37,000 PDB ligands and 7560 DrugBank molecules, integrates more than 6000 small-molecule-associated post-translational modifications, and provides context for 14,000 + PTM-modified human protein models featuring docked ligands. The database encompasses 43,023 unique UniProt accessions and 174,545 PDB structures. The DrugDomain data is available online: https://drugdomain.cs.ucf.edu/ and https://github.com/kirmedvedev/DrugDomain.

Keywords: Database; Drug discovery; Drugs; Protein domains; Protein-drug interaction; Small molecules.

Graphical abstract

Fig. 1

DrugDomain database v2.0 data types and statistics.

Fig. 2

DrugDomain v2.0 statistics. (A) Taxonomic distribution of proteins reported in the DrugDomain database, by UniProt population. The inside pie shows the distribution of super kingdoms, and the outside donut shows the distribution of phyla. (B) Distribution of ECOD domains from experimentally determined PDB structures, interacting with ligand, stratified by architecture (inside pie) and homologous group (outside donut).

Fig. 3

ECOD A-groups (left column) of experimental PDB structures and superclasses of organic molecules according to ClassyFire classification (right column). Each superclass and the lines pointed toward it are denoted by separate color. The thickness of the lines shows the number of PDB ligands interacting with domains from ECOD A-groups.

Fig. 4

Ligand-interacting statistics by number of domains per UniProt accession in Protein Data Bank. The left column shows the number of ligand-interacting domains, the right column shows the superclasses of organic molecules according to ClassyFire classification. The thickness of the lines indicates the number of UniProt accessions.

Fig. 5

Structure of the human mitochondrial Mrs2 channel (PDB: 8IP5). (A) Channel view of Mrs2 with protein colored by ECOD domains, Mg^2 + ion is shown in green, and sticks show interacting residues. (B) Close-up channel view of Mrs2. (C) Side view of Mrs2 showing three out of five monomers. Chains C, D, and E are colored by ECOD domains.

Fig. 6

Examples of ATP binding to different proteins. (A) Ubiquitin-like modifier-activating enzyme Atg7 bound to Atg8 (PDB: 3VH4). (B) Cobalamin adenosyltransferase MMAB (PDB: 6D5K). (C) ATP-binding cassette transporter ABCG2 (PDB: 6HZM) (D) ATP phosphoribosyltransferase (PDB: 5UBH). All proteins are colored by their ECOD domains. ATP is depicted with sticks and colored by its constituent elements. Residues interacting with ATP are colored in magenta.