Mining the Protein Data Bank to inspire fragment library design

Abstract

The fragment approach has emerged as a method of choice for drug design, as it allows difficult therapeutic targets to be addressed. Success lies in the choice of the screened chemical library and the biophysical screening method, and also in the quality of the selected fragment and structural information used to develop a drug-like ligand. It has recently been proposed that promiscuous compounds, i.e., those that bind to several proteins, present an advantage for the fragment approach because they are likely to give frequent hits in screening. In this study, we searched the Protein Data Bank for fragments with multiple binding modes and targeting different sites. We identified 203 fragments represented by 90 scaffolds, some of which are not or hardly present in commercial fragment libraries. By contrast to other available fragment libraries, the studied set is enriched in fragments with a marked three-dimensional character (download at 10.5281/zenodo.7554649).

Keywords: FBDD; PDB; binding mode; interaction graph; scaffold; similarity; site comparison.