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.

FIGURE 1

Overall workflow.

FIGURE 2

Properties of the versatile PDB fragments. (A) Molecular weight vs. AlogP (B) Number of rings (C) PBF vs. Number of rotatable bonds (D) Number of binding modes vs. Number of binding cavities. The distributions of individual properties are given on the top and side of the heat maps in (A), (C) and (D). The color scale on the side of the heat maps in (A), (C) and (D) refers to the number of fragments.

FIGURE 3

Examples of three-dimensional structures of PDB versatile fragments (A) Interactions formed by pyrrolo-pyrimidine in tRNA-guanine transglycolase and nitryl reductase QueF. (B) Substituted furanone binding to two adjacent subpockets in strigolactone esterase D14. The cavity points representing the two subpockets and used for the comparison of the two sites are shown in the left image.

FIGURE 4

Representative chemical structures of the versatile PDB fragments which are absent or poorly represented in commercial fragments libraries. Below each fragment structure are indicated the HET code, then the number of binding modes/the number of different cavities/the number of versatile PDB fragments containing the same scaffold/the number of commercial fragments containing the same scaffold.

FIGURE 5

Spatial distribution of the fragments in GTM Landscapes (A) Versatile PDB fragments (B) All commercially-available fragments (C) Ensemble of nature-product like commercial libraries. (D) Examples of versatile PDB fragments. Their projection points are marked with blue dots on the map (A). Figures 5B, C are adapted from (Revillo Imbernon et al., 2022).