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August 15, 2026ACS Chemical Biology

Systematic Virtual Screening of Heparan Sulfate Oligosaccharides and Mechanistic Insights into Heparanase Inhibition

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Authors

BLBinjie LiSZSiran ZhaoZLZongLin Lan

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Overview

Computational screening reveals specific sulfation motifs governing heparanase inhibition, indicating a rational design strategy for glycan therapeutics.

Key Points

  • To discover novel heparanase inhibitors by developing a comprehensive virtual library of heparan sulfate oligosaccharides and elucidating their structural binding mechanisms.
  • Constructed a rule-based database of heparan sulfate oligosaccharides (disaccharides to hexasaccharides) encompassing diverse sulfation patterns and stereochemical configurations.
  • Performed multistage virtual screening against heparanase, evaluated systematic desulfation of lead candidate HP-dp5R1, and modeled interactions using molecular dynamics simulations.
  • Even- and odd-numbered oligosaccharides exhibited distinct binding motifs, with odd-numbered chains enriched in IdoA2S and GlcN3S6S sequences.
  • Selective removal of 2-O- or 3-O-sulfate groups caused substantially larger binding-free energy penalties than removing 6-O- or N-sulfates, demonstrating their critical role in target recognition.
  • Longer oligosaccharide chains engaged both flanking heparin-binding domains (HBD1 and HBD2), leading to marked reductions in conformational fluctuation.

Cite This Study

Li et al. (2026) studied this question.

synapsesocial.com/papers/6a8019f175c2e31742c862eahttps://doi.org/10.1021/acschembio.6c00454
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Also Consider

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  1. 1Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study2024 · 8 citations
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  3. 3A Novel Marine Bacterium-Derived Heparinase with High Potential for the Structure–Function Studies of Heparin/Heparan Sulfate2025
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  5. 5Development of a sensitive and specific method to measure heparanase activity in complex biological matrices2026 · 2 citations