MLN-4760

A variety of sulfur‐containing small molecules can be found in the spears of asparagus (Asparagus Officinalis L.) including compounds derived from asparagusic acid such as the amino acid derivatives asparaptines A, B, and C. The previous characterization of asparaptine A as an inhibitor of angiotensin‐converting enzyme (ACE) prompted us to compare the binding of the three asparaptines to ACE2 using molecular modeling. The lysine conjugate asparaptine B was found to bind better to the enzyme than the arginine (asparaptine A) and histidine (asparaptine C) conjugates. The stability of ACE2‐asparaptine B complexes was only a little inferior to that observed with the reference ACE2 inhibitor MLN‐4760. On this basis, 20 additional compounds bearing a thiol group or a dithiolane motif were evaluated as potential binders to ACE2 using the same docking methodology. Three compounds emerged as robust ACE2 binders: the natural products isovalthine and N‐acetyl‐felinine, and the drug candidate CMX‐2043. The empirical energy of interaction (ΔE) of N‐acetyl‐felinine with ACE2 was comparable to that measured with asparaptine B, and a little higher with the thiol metabolite isovalthine. Remarkably, CMX‐2043 revealed a high capacity to form stable complexes with ACE2, superior to that of the reference MLN‐4760. Both the l‐Glu‐l‐Ala dipeptide motif and the α‐lipoic acid moiety of CMX‐2043 are implicated in the protein interaction. Our observations pave the way to the design of novel ligands of ACE2 equipped with a dithiolane motif.