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A Selectivity Study of FFAR4/FFAR1 Agonists by Molecular Modeling
journal contribution
posted on 2019-10-16, 22:16 authored by Xiangying Zhang, Hongbin Sun, Xiaoan Wen, Haoliang YuanFFAR4 has been considered
as a potential target for metabolic diseases,
including diabetes. Some compounds with biphenyl scaffold, represented
by compound SR13 reported by our group, showed significant
FFAR4 selectivity. However, the molecular basis for their selectivity
has not been definitely disclosed. This study provided insights into
the protein–ligand interactions between agonists and FFAR4/FFAR1
by molecular modeling. The important residues identified were consistent
with those found in experimental studies. Moreover, the results proposed
that the selectivity of SR13 between FFAR4 and FFAR1
depended on whether it can enter the ligand-binding site through the
entrance region by adopting its preferential conformation. The big
difference between the preferential conformation of SR13 and the narrow entrance region determined its poor agonist activity
against FFAR1. These findings will facilitate the further development
of selective FFAR4 agonists.