8DXG

HIV-1 reverse transcriptase/rilpivirine with bound fragment 5-(trifluoromethyl)pyridin-2-ol at W24 site

Summary for 8DXG

• Entry DOI: 10.2210/pdb8dxg/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, 5-(trifluoromethyl)pyridin-2-one, ... (9 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase, transferase
• Biological source: Human immunodeficiency virus type 1 BH10; More
• Total number of polymer chains: 2
• Total formula weight: 115760.14

Authors

Chopra, A.,Ruiz, F.X.,Bauman, J.D.,Arnold, E. (deposition date: 2022-08-02, release date: 2023-05-31, Last modification date: 2023-10-25)

Primary citation

Chopra, A.,Bauman, J.D.,Ruiz, F.X.,Arnold, E.
Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.
J.Med.Chem., 66:6013-6024, 2023

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.

PubMed: 37115705
DOI: 10.1021/acs.jmedchem.2c01681

Experimental method

X-RAY DIFFRACTION (2.1 Å)