Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors.
We describe a series of potent and selective inhibitors of ADAM12 that were discovered using computational screening of a focused virtual library. The initial structure-based virtual screening selected 64 compounds from a 3D database of 67,062 molecules. Being evaluated by a cell-based ADAM12 activity assay, compounds 5, 11, 14, 16 were further identified as the potent and selective inhibitors of ADAM12 with low nanomolar IC50 values. The mechanism underlying the potency and selectivity of a representative compound, 5, was investigated through molecular docking studies.
Oh
Myungsok
M
Department of Life Science and National Research Laboratory of Proteolysis, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Im
Isak
I
Lee
Yong Jae
YJ
Kim
Young Hoon
YH
Yoon
Jeong Hyeok
JH
Park
Hye Gyeong
HG
Higashiyama
Shigeki
S
Kim
Yong-Chul
YC
Park
Woo Jin
WJ
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D008565:Membrane Proteins; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072199:ADAM12 Protein; D008666:Metalloendopeptidases