User-centric design of a 3D search interface for protein-ligand complexes.

In this work, we present the frontend of GeoMine and showcase its application, focusing on the new features of its latest version. GeoMine is a search engine for ligand-bound and predicted empty binding sites in the Protein Data Bank. In addition to its basic text-based search functionalities, GeoMine offers a geometric query type for searching binding sites with a specific relative spatial arrangement of chemical features such as heavy atoms and intermolecular interactions. In contrast to a text search that requires simple and easy-to-formulate user input, a 3D input is more complex, and its specification can be challenging for users. GeoMine's new version aims to address this issue from the graphical user interface perspective by introducing an additional visualization concept and a new query template type. In its latest version, GeoMine extends its query-building capabilities primarily through input formulation in 2D. The 2D editor is fully synchronized with GeoMine's 3D editor and provides the same functionality. It enables template-free query generation and template-based query selection directly in 2D pose diagrams. In addition, the query generation with the 3D editor now supports predicted empty binding sites for AlphaFold structures as query templates. GeoMine is freely accessible on the ProteinsPlus web server ( https://proteins.plus ).

Searching Geometric Patterns in Protein Binding Sites and Their Application to Data Mining in Protein Kinase Structures.

The ever-growing number of protein-ligand complex structures can give fundamental insights into protein functions and protein-ligand interactions, especially in the field of protein kinase research. The number of tools to mine this data for individually defined structural motifs is restricted due to the challenging task of developing efficient index structures for 3D data in relational databases. Herein we present GeoMine, a database system with web front-end mining of more than 900 000 binding sites. It enables database searches for geometric (interaction) patterns in protein-ligand interfaces by, for example, textual, numerical, substructure, similarity, and 3D searches. GeoMine processes reasonably selective user-defined queries within minutes. We demonstrate its usability for advancing protein kinase research with a special emphasis on unusual interactions, their use in designing selective kinase inhibitors, and the analysis of reactive cysteine residues that are amenable to covalent kinase inhibitors. GeoMine is freely available as part of our modeling support server at https://proteins.plus.