从虚拟筛选到细胞靶标参与:免疫检查点 LAG-3 的新小分子配体

Natalie Fuchs, Laura Calvo-Barreiro, Valerij Talagayev, Szymon Pach, Gerhard Wolber, Moustafa T. Gabr
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摘要

在此,我们进行了一项虚拟筛选研究,以发现基于小分子的免疫检查点淋巴细胞活化基因 3(LAG-3)配体的新支架。利用 LAG-3 结构进行的分子动力学(MD)模拟揭示了小分子的两个潜在结合位点:抗体界面和亲油峡谷。通过三维药理筛选,我们确定了这些结合位点的潜在配体,并建立了一个由 25 种化合物组成的化合物库。然后,我们通过微尺度热泳(MST)和表面等离子体共振(SPR)评估了筛选出的 LAG-3 结合情况。我们的生物物理筛选确定了两种 KD 值在低微摩尔范围内的结合剂,即化合物 3(抗体界面)和 25(亲油峡谷)。此外,我们还利用细胞热转移试验(CETSA)研究了 LAG-3 命中化合物在细胞水平上诱导 LAG-3 的能力,结果发现化合物 3 有希望成为未来开发的候选化合物。
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From Virtual Screens to Cellular Target Engagement: New Small Molecule Ligands for the Immune Checkpoint LAG-3
Herein, we performed a virtual screening study to discover new scaffolds for small molecule-based ligands of the immune checkpoint lymphocyte-activation gene 3 (LAG-3). Molecular dynamics (MD) simulations using the LAG-3 structure revealed two putative binding sites for small molecules: the antibody interface and a lipophilic canyon. A 3D pharmacophore screening resulted in the identification of potential ligands for these binding sites and afforded a library of 25 compounds. We then evaluated the screening hits for LAG-3 binding via microscale thermophoresis (MST) and surface plasmon resonance (SPR). Our biophysical screening identified two binders with KD values in the low micromolar range, compounds 3 (antibody interface) and 25 (lipophilic canyon). Furthermore, we investigated the ability of LAG-3 hits to en-gage LAG-3 on a cellular level using a cellular thermal shift assay (CETSA), where compound 3 emerged as a promising candidate for future development.
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