Fuchs Natalie, Calvo-Barreiro Laura, Talagayev Valerij, Pach Szymon, Wolber Gerhard, Gabr Moustafa T
Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, Germany.
ACS Med Chem Lett. 2024 Oct 15;15(11):1884-1890. doi: 10.1021/acsmedchemlett.4c00350. eCollection 2024 Nov 14.
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 the 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 values in the low micromolar range, compounds (antibody interface) and (lipophilic canyon). Furthermore, we investigated the ability of LAG-3 hits to engage LAG-3 on a cellular level using a cellular thermal shift assay (CETSA). In summary, compound shows potential as a lead but is not yet a development candidate.
在此，我们进行了一项虚拟筛选研究，以发现用于免疫检查点淋巴细胞激活基因3（LAG-3）的小分子配体的新骨架。使用LAG-3结构进行的分子动力学（MD）模拟揭示了小分子的两个假定结合位点：抗体界面和亲脂性峡谷。三维药效团筛选导致鉴定出这些结合位点的潜在配体，并提供了一个包含25种化合物的文库。然后，我们通过微量热泳动（MST）和表面等离子体共振（SPR）评估了筛选出的化合物与LAG-3的结合情况。我们的生物物理筛选确定了两种结合剂，其解离常数在低微摩尔范围内，即化合物 （抗体界面）和 （亲脂性峡谷）。此外，我们使用细胞热位移分析（CETSA）在细胞水平上研究了筛选出的与LAG-3结合的化合物与LAG-3结合的能力。总之，化合物 显示出作为先导化合物的潜力，但尚未成为开发候选物。
