%0 Journal Article
%T Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design.
%A Yu S
%A Huang W
%A Zhang H
%A Guo Y
%A Zhang B
%A Zhang G
%A Lei J
%J Eur J Med Chem
%V 271
%N 0
%D 2024 May 5
%M 38677061
%F 7.088
%R 10.1016/j.ejmech.2024.116414
%X Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/β-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a Kd value of 42.43 nM against sclerostin loop3. The simplification and derivation of THFA using molecular modeling-guided modification allowed the discovery of an effective and loop3-selective small molecular inhibitor, compound (4-(3-acetamidoprop-1-yn-1-yl)benzoyl)glycine (AACA), with improved binding affinity (Kd = 15.4 nM) compared to the hit THFA. Further in-vitro experiment revealed that compound AACA could attenuate the suppressive effect of transfected sclerostin on Wnt signaling and bone formation. These results make AACA as a potential candidate for development of anti-osteoporosis agents without increasing cardiovascular risk.