@article {1652765,
	title = {A general chemical principle for creating closure-stabilizing integrin inhibitors},
	journal = {Cell},
	volume = {185},
	number = {19},
	year = {2022},
	month = {2022 Sep 15},
	pages = {3533-3550.e27},
	abstract = {Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.},
	keywords = {Drug Design, Integrin alpha4beta1, Protein Conformation, Serine, Water},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2022.08.008},
	author = {Lin, Fu-Yang and Li, Jing and Xie, Yonghua and Zhu, Jianghai and Huong Nguyen, Thi Thu and Zhang, Yonghui and Zhu, Jieqing and Springer, Timothy A.}
}
