An NMR-based fragment screening approach to identify LCAT modulators

Authors

• EM Hausmann
• SA Kotler
• SL Saldana-Shumaker
• MG Seidel
• BR Woodward
• M Fletcher
• JW Carter
• MI Konaklieva
• CA LeClair

Abstract

Atherosclerotic cardiovascular disease (ASCVD), which involves the buildup of cholesterol-containing plaque in the arteries, encompasses a range of cardiovascular conditions that are the leading cause of death in the world. Lecithin:cholesterol acyltransferase (LCAT) is an enzyme that drives maturation of HDL particles to HDL-C. Low HDL-C levels are associated with increased risk of ASCVD. The development of novel therapies that improve LCAT function are necessary for the treatment of cardiovascular disease, as well as rare diseases like familial LCAT deficiency (FLD) and fish-eye disease. Our aim was to identify new small molecules that bind LCAT and modulate its activity through NMR-based fragment screening methods. A curated library of rationally designed fragments was screened against LCAT to identify reversible binders. These fragments were subsequently subjected to two competitive screens. The first involved a compound known to bind the membrane-binding domain (MBD) of the enzyme (Manthei, K. A. et al., eLife 7, e41604 (2018).) and the second utilized isopropyl dodecylfluorophosphonate (IDFP), which irreversibly binds the catalytic serine in the active site. Observed changes in binding between the initial screen and the competition screens should provide information on fragment binding location and relative binding strength. Synthetic elaboration of the fragment hits guided by NMR data will afford a ligand that is, ideally, more potent and selective than the initial fragment, while retaining drug-like physical properties.

Scientific Focus Area: Biomedical Engineering and Biophysics

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