Identification of Novel Cyclobutane-Based Derivatives as Potent Acetyl-CoA Carboxylase Allosteric Inhibitors for Nonalcoholic Steatohepatitis Drug Discovery

Nonalcoholic
steatohepatitis (NASH) has become a leading cause
of liver fibrosis and hepatocellular carcinoma; however, there are
no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC)
is a crucial enzyme regulating lipid metabolism that is considered
as a potential target for NASH treatment. Allosteric inhibitors target
nonfunctional sites, which tend to be highly variable in protein families;
thus, allosteric inhibitors are explored as an important source of
drug candidates. Herein, several hotspot residues are initially identified
by utilizing molecular dynamic simulation, MM-GBSA calculation, and
alanine mutation. Then, focusing on the interaction with hotspot residues,
several cyclobutane-based ACC allosteric inhibitors are designed,
synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent
therapeutic effect for NASH in vivo, making it a
promising candidate for the treatment of NASH.