Download MendeleyHalo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.
Chopra, A., Bauman, J.D., Ruiz, F.X., Arnold, E.(2023) J Med Chem 66: 6013-6024
- PubMed: 37115705
- DOI: https://doi.org/10.1021/acs.jmedchem.2c01681
- Primary Citation of Related Structures:
8DX2, 8DX3, 8DX8, 8DXB, 8DXE, 8DXG, 8DXH, 8DXI, 8DXJ, 8DXK, 8DXL, 8DXM - PubMed Abstract:
X-ray crystallographic fragment screening (XCFS) uses fragment-sized molecules (∼60 to 300 Da) to access binding sites on proteins that may be inaccessible to larger drug-like molecules (>300 Da). Previous studies have shown that fragments containing halogen atoms bind more often to proteins than non-halogenated fragments. Here, we designed the Halo Library containing 46 halogenated fragments (including the "universal fragment" 4-bromopyrazole), a majority of which have been reported to bind to or inhibit one or more targets. The library was screened against the crystals of HIV-1 reverse transcriptase with the drug rilpivirine, yielding an overall hit rate of 26%. Two new binding sites were discovered, and several hot spots were identified. This small library may thus provide a convenient tool for rapidly assessing the feasibility of a target for XCFS, mapping hot spots and cryptic sites, as well as finding fragment binders that can be useful for developing drug leads.
Organizational Affiliation:
Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, United States.
