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发现ICOS向的小分子,使用基于药的查

Laura Calvo-Barreiro¹, Valerij Talagayev², Szymon Pach²

¹Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY-10065, USA.

|October 16, 2023

概括

研究人员开发了一种虚拟查策略,以找到小分子免疫检查点调节器. 这种方法确定了可诱导共刺激剂 (ICOS) 的新型小分子结合剂,为新的癌症疗法铺平了道路.

科学领域:

药物发现和开发药物发现和开发
免疫学免疫学免疫学
计算化学计算化学

背景情况:

小分子在免疫检查点调节方面比单克隆抗体 (mAbs) 有优势,包括口服生物可用性和改善瘤透.
诱导性共刺激剂 (ICOS) 和它的配体 (ICOS-L) 对于T细胞分化和B细胞激活至关重要.
目前,没有小分子被临床批准作为免疫检查点调节器.

研究的目的:

开发和验证一种虚拟选策略,用于识别向人类ICOS中新型结合口袋的小分子.
为了发现一流的小分子ICOS结合剂.
为ICOS准的小分子建立生物物理选平台.

主要方法:

在ICOS的apo结构和ICOS/ICOS-L接口上利用了分子动力学模拟来生成3D药.
采用基于已识别的药理分子的虚拟选活动.
使用生物物理查平台验证的发现.

主要成果:

成功开发并验证了小分子ICOS结合剂的虚拟选策略.
确定了一种类中的第一个小分子ICOS结合剂,被指定为5P,K_D值为108.08±26.76μM.
证实了生物物理查平台的实用性,用于评估ICOS向的小分子.

结论:

开发的虚拟选策略对于发现小分子ICOS结合物的有效.
已识别的小分子5P代表了进一步优化的一个有希望的起点.
未来5P的结构优化预计将为ICOS产生高亲和度化学配体,可能导致新的癌症免疫疗法.

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