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<p>The human Y-box binding protein (YB-1) is a multifaceted protein that plays a crucial role in the progression of diseases such as HIV, cancer, and therapy resistance. The absence of a resolved three-dimensional structure of YB-1 has hindered efforts to design potential allosteric modulators targeting full protein. Our study unveils the first comprehensive structural model of YB-1 protein. We validated this structure via 300&#xa0;ns molecular dynamics (MD) simulations and mapped the YB-1 interaction protein (PPIs) network to better understand its role in disease progression. Then, we designed four 1,4-naphthoquinone analogues as potential YB-1 small molecule modulators and evaluated their drug-like properties. Among them, AIGM-2024–4 showed favorable binding affinity with YB-1, and its interaction stability assessed through 300&#xa0;ns MD. We synthesized this modulator utilizing chemo-selective functionalization and confirmed its interactions with recombinant full-length YB-1 protein validated through Microscale Thermophoresis (MST). The biophysical interaction validation confirms our in silico investigations, with AIGM-2024–4 demonstrating a ̴15.8% higher binding affinity with YB-1 compared to a control molecule, fisetin. Thus, AIGM-2024–4 shows promise for developing a new class of YB-1 inhibitors for the treatment of diseases associated with YB-1.</p>

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Discovery of a Novel Small-Molecule Modulator for Full-length YB-1 Protein via Integrated Computational and in vitro Biophysical Approaches

  • 期刊论文

  • 发表日期：

    2026年1月20日

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  • Maharaja Somasundaram,
  • Pandaram Sakthivel,
  • Sakthi Sasikala Sundaravel,
  • Sneha Jos,
  • Karthikeyan Muthusamy,
  • Sivaraman Thirunavukkarasu,
  • Ilangovan Andivelu,
  • Mathan Ganeshan

摘要

The human Y-box binding protein (YB-1) is a multifaceted protein that plays a crucial role in the progression of diseases such as HIV, cancer, and therapy resistance. The absence of a resolved three-dimensional structure of YB-1 has hindered efforts to design potential allosteric modulators targeting full protein. Our study unveils the first comprehensive structural model of YB-1 protein. We validated this structure via 300 ns molecular dynamics (MD) simulations and mapped the YB-1 interaction protein (PPIs) network to better understand its role in disease progression. Then, we designed four 1,4-naphthoquinone analogues as potential YB-1 small molecule modulators and evaluated their drug-like properties. Among them, AIGM-2024–4 showed favorable binding affinity with YB-1, and its interaction stability assessed through 300 ns MD. We synthesized this modulator utilizing chemo-selective functionalization and confirmed its interactions with recombinant full-length YB-1 protein validated through Microscale Thermophoresis (MST). The biophysical interaction validation confirms our in silico investigations, with AIGM-2024–4 demonstrating a ̴15.8% higher binding affinity with YB-1 compared to a control molecule, fisetin. Thus, AIGM-2024–4 shows promise for developing a new class of YB-1 inhibitors for the treatment of diseases associated with YB-1.