# X-ray Crystallographic Fragment Screening Core

> **NIH NIH U54** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $366,871

## Abstract

Abstract
 X-ray crystallographic fragment screening (XCFS) is a powerful tool for identification of new pharmacophores
for probes and drug design as well as well as for biochemical and structural dynamic characterization of the
protein of interest. An XCFS Core has been established to make this powerful tool accessible to multiple HIVE
Projects studying HIV-1 and related proteins/complexes in the HIVE. The XCFS Core (Arnold group) has
completed three XCFS campaigns against the viral targets: HIV-1 reverse transcriptase, influenza A
endonuclease, and HIV-1 integrase catalytic core domain. In each case the successful screening campaign
has discovered novel hits and in the cases of HIV-1 reverse transcriptase and influenza endonuclease has
found novel conformations/pockets for understanding protein dynamics and biochemistry.
 The XCFS Core will collaborate with the other HIVE Projects and Cores to identify crystal forms that are
appropriate for XCFS and optimize them as needed. Initial projects include: HIV-1 capsid (Project 3,
Sarafianos), HIV-1 integrase (Projects 1 and 4, Kvaratskhelia and Engelman), and HIV-1 reverse
transcriptase with nucleic acid substrate (Project 3, Arnold). Small pilot screening will verify the usefulness of
the crystal form for XCFS before proceeding to large scale screening using very high-throughput synchrotron
X-ray crystallography beamlines (Specific Aim 1). A specialized beamline, XChem, at the Diamond Light
Source will be used to efficiently and rapidly screen 1000-2000 small molecule fragments. The XChem facility
has developed several technologies for fragment soaking, crystal handling, data collection and processing to
allow for very rapid XCFS campaigns. In addition to XChem, there are new high-speed beamlines at
Brookhaven National Laboratories and elsewhere capable of data-collection speeds unobtainable two years
ago. The new beamline technologies allow for fragments from a large library to be screened individually,
whereas previously mixtures of fragments needed to be used. The ability to screen individual compounds
allows for design of novel compound libraries to take advantage of this new technology (Specific Aim 2). New
fragment libraries with click-reactive and SuFEx-containing moieties will be designed for XCFS (Project 6,
Olson and Sharpless).
 Data from XCFS will be processed and refined to ensure accurate hit identification and hits will be verified
through screening of derivatives and appropriate orthogonal assays. Communication and data management
between the Projects and Cores will ensure clear information transfer and follow up chemistry/studies (Specific
Aim 3).

## Key facts

- **NIH application ID:** 10242904
- **Project number:** 5U54AI150472-11
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** EDWARD ARNOLD
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,871
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242904

## Citation

> US National Institutes of Health, RePORTER application 10242904, X-ray Crystallographic Fragment Screening Core (5U54AI150472-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242904. Licensed CC0.

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