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
• Publication Date: 2024-04-06T10:36:06Z
• Authors: Stuart Lang; Daniel A. Fletcher; Alain‐Pierre Petit; Nicola Luise; Paul Fyfe; Fabio Zuccotto; David Porter; Anthony Hope; Fiona Bellany; Catrina Kerr; Claire J. Mackenzie; Paul G. Wyatt; David W. Gray
• Keywords: Models, Molecular; 570; Structure-Activity Relationship; Binding Sites; Magnetic Resonance Spectroscopy; Molecular Structure; Anti-HIV Agents; Drug Discovery; HIV-1; Humans; Capsid Proteins; Crystallography, X-Ray; Protein Binding

AbstractIdentification 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.