Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI:10.1021/acsmedchemlett.5c0007110.1021/acsmedchemlett.5c00071

Nitesh Mani Tripathi, Arnab Chowdhury, Neelam Verma and Anupam Bandyopadhyay*,

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Abstract

Here we harnessed the unexplored binding interface between the 16-residue peptide (P) agonist and death receptor 5 (DR5). P is a solitary peptide ligand that mimics TRAIL (the natural ligand to death receptor) and is reported to control cancer growth in vivo selectively. We delved into the strategic merging of experimental and in silico structure–activity studies via the alanine scanning mutagenesis of P, wherein the disulfide bond was kept intact for structural integrity. Antiproliferative activity studies with these synthetic mutants on HCT116 cells enabled the mapping of the interaction engagement of each residue. Further, in silico docking and MD simulations led us to interpret and model the 3D interface of the binding site. Notably, Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected experimentally as “hot-spot” residues crucial for primary interactions with DR5, which is predominantly supported via in silico investigations. This study is pivotal for developing new-generation peptide agonists that induce death receptor-mediated apoptosis.

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通过丙氨酸扫描介绍trail模拟肽与DR5之间的潜在结合界面

在这里，我们利用了16残基肽(P)激动剂和死亡受体5 （DR5）之间未被探索的结合界面。P是一种孤立肽配体，模仿TRAIL（天然的死亡受体配体），据报道在体内选择性地控制癌症的生长。我们通过P的丙氨酸扫描诱变深入研究了实验和硅结构-活性研究的战略合并，其中二硫键保持完整的结构完整性。这些合成突变体在HCT116细胞上的抗增殖活性研究使每个残基的相互作用参与图谱成为可能。此外，在硅对接和MD模拟使我们能够解释和建模结合位点的三维界面。值得注意的是，Trp1、Leu4、Arg7、Ile8、Gln12和Arg15在实验中被预测为与DR5主要相互作用的关键“热点”残基，这主要是通过硅研究得到的支持。这项研究对于开发新一代肽激动剂诱导死亡受体介导的细胞凋亡至关重要。

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.