基于结构的虚拟筛选的吡唑骨架蛋白酶体抑制剂。
Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
出版信息
J Med Chem. 2015 Feb 26;58(4):2036-41. doi: 10.1021/jm501344n. Epub 2015 Feb 17.
Abstract
We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.
摘要
我们对蛋白酶体的活性位点进行了约 340000 种小分子的虚拟筛选，随后进行了体外检测和后续优化，得到了一种具有吡唑骨架的蛋白酶体抑制剂。该吡唑骨架化合物具有优异的代谢稳定性，并在体内有效地抑制了实体肿瘤的生长。此外，该化合物的有效性不受硼替佐米或卡非佐米耐药性的影响。
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