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Application of an NMR/crystallography fragment screening platform for the assessment and rapid discovery of new HIV‐CA binding fragments

DOI: 10.1002/cmdc.202400025 DOI Help

Authors: Stuart Lang (University of Dundee) , Dan A. Fletcher (University of Dundee) , Alain-Pierre Petit (University of Dundee) , Nicola Luise (University of Dundee) , Paul K. Fyfe (University of Dundee) , Fabio Zuccotto (University of Dundee) , David Porter (University of Dundee) , Anthony Hope (University of Dundee) , Fiona Bellany (University of Dundee) , Catrina Kerr (University of Dundee) , Claire J. Mackenzie (University of Dundee) , Paul G. Wyatt (University of Dundee) , David W. Gray (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: April 2024
Diamond Proposal Number(s): 19844

Abstract: Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 08/04/2024 09:05

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)