From Virtual Screens to Cellular Target Engagement: New Small Molecule Ligands for the Immune Checkpoint LAG-3.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-15 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00350

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

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Abstract

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 K _D values in the low micromolar range, compounds 3 (antibody interface) and 25 (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 3 shows potential as a lead but is not yet a development candidate.

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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。

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 K D 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与 LAG-3 结合的能力。总之，化合物 3 显示出作为先导物的潜力，但尚未成为候选开发物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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