PDBsum entry 6q4c

Cell cycle

PDB id: 6q4c

Contents

Protein chain

293 a.a.

Ligands

HH8

Waters ×230

References listed in PDB file

Key reference

• Title: Fraglites-Minimal, Halogenated fragments displaying pharmacophore doublets. An efficient approach to druggability assessment and hit generation.
• Authors: D.J.Wood, J.D.Lopez-Fernandez, L.E.Knight, I.Al-Khawaldeh, C.Gai, S.Lin, M.P.Martin, D.C.Miller, C.Cano, J.A.Endicott, I.R.Hardcastle, M.E.M.Noble, M.J.Waring.
• Ref.: J Med Chem, 2019, 62, 3741-3752. [DOI no: 10.1021/acs.jmedchem.9b00304]
• PubMed id: 30860382

Abstract

Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource-intensive screening of large libraries of lead-like or fragment molecules. Here, we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence, the approach provides a new method of identifying ligand sites, assessing tractability and discovering new leads.