PDBsum entry 4c3f

Transferase

PDB id: 4c3f

Contents

Protein chain

257 a.a.

Ligands

7KW

Waters ×355

References listed in PDB file

Key reference

• Title: Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes.
• Authors: A.M.Wassermann, P.S.Kutchukian, E.Lounkine, T.Luethi, J.Hamon, M.T.Bocker, H.A.Malik, S.W.Cowan-Jacob, M.Glick.
• Ref.: J Med Chem, 2013, 56, 8879-8891. [DOI no: 10.1021/jm401309q]
• PubMed id: 24117015

Abstract

We introduce a novel strategy to sample bioactive chemical space, which follows-up on hits from fragment campaigns without the need for a crystal structure. Our results strongly suggest that screening a few hundred or thousand fragments can substantially improve the selection of small-molecule screening subsets. By combining fragment-based screening with virtual fragment linking and HTS fingerprints, we have developed an effective strategy not only to expand from low-affinity hits to potent compounds but also to hop in chemical space to substantially novel chemotypes. In benchmark calculations, our approach accessed subsets of compounds that were substantially enriched in chemically diverse hit compounds for various activity classes. Overall, half of the hits in the screening collection were found by screening only 10% of the library. Furthermore, a prospective application led to the discovery of two structurally novel histone deacetylase 4 inhibitors.