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).

Developments in the chemistry and biology of 1,2,3‐triazolyl‐C‐nucleosides

“…As an example of its pleiotropic mechanism of action, RBV was recently identified as a multiple bonding-mode fragment in a computational fragment drug design approach. [66] It is reasonable to hypothesize that all such nucleoside RBV analogs, including showdomycin and pyrazofurin, also act by pleiotropic mechanisms since they also revealed broad-spectrum activities. Regarding 1,2,3-triazolyl-N-ribosides, they show antiviral activities against several types of viruses [30,67] and have been extensively studied for biological properties.…”