Abstract

In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of β-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein.

Graphic Abstract

中文翻译：

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基于结构的膳食食品多酚中 galectin-1 选择性调节剂的鉴定：一种药物信息学方法

摘要

在这项研究中，综合研究了一组膳食多酚，用于选择性鉴定 galectin-1 的潜在抑制剂/调节剂。Galectin-1 是肿瘤进展的有效预后指标，也是各种病理状况的高度重视的治疗靶点。该指标由一个高度保守的碳水化合物识别结构域 (CRD) 组成，它解释了 β-半乳糖苷的结合亲和力。尽管一些小分子已被鉴定为 galectin-1 抑制剂/调节剂，但针对这一有吸引力的治疗靶点的新型化合物的鉴定研究有限。广泛的计算技术包括对 galectin-1 的潜在药物结合位点识别、约 500 种多酚的结合亲和力预测、分子对接、和具有选择性膳食多酚调节剂的半乳糖凝集素-1 的动态模拟，然后估计结合自由能以鉴定膳食多酚基半乳糖凝集素-1 调节剂。最初，基于深度神经网络的算法用于预测药物结合位点和结合亲和力。此后，通过超精密对接技术对多酚化合物与半乳糖凝集素-1的分子间相互作用进行了批判性探索。此外，通过传统的原子 100 ns 动态模拟研究评估了相互作用的稳定性。对接分析表明，galectin-1 的 CRD 区域的不同氨基酸与所提出的五种多酚具有高相互作用亲和力。从所选膳食多酚在动态条件下的模拟轨迹中可以看出强烈且一致的相互作用稳定性。此外，保守残基（His44、Asn46、Arg48、Val59、Asn61、Trp68、Glu71 和 Arg73）关联表明多酚对 galectin-1 蛋白具有高亲和力和选择性。

图形摘要