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Heparanase is an\n                    <jats:italic>endo<\/jats:italic>\n                    \u2010\u03b2\u2010glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS\u2212CoV\u20102. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end \u03b2\u2010D\u2010glucose residue of PG545 adopts a distorted conformation. This was followed by docking and molecular dynamics simulations to study the interactions of PG545 with heparanase, revealing that PG545 is able to block the active site by binding in different conformations, with the cholestanol side\u2010chain making important hydrophobic interactions. While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next\u2010generation heparanase inhibitors and substrates.\n                  <\/jats:p>","DOI":"10.1002\/chem.202104222","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T22:18:54Z","timestamp":1641248334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6716-7580","authenticated-orcid":false,"given":"Mohit","family":"Chhabra","sequence":"first","affiliation":[{"name":"School of Chemistry &amp; Molecular Biosciences The University of Queensland  Brisbane Queensland 4072 Australia"},{"name":"Australian Infectious Diseases Research Centre The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6475-3381","authenticated-orcid":false,"given":"Jennifer C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Science Griffith University Gold Coast Campus  Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0294-7065","authenticated-orcid":false,"given":"Liang","family":"Wu","sequence":"additional","affiliation":[{"name":"The Rosalind Franklin Institute Harwell Campus  Didcot OX11 0FA UK"},{"name":"Department of Chemistry University of York Heslington  York YO10 5DD UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7343-776X","authenticated-orcid":false,"given":"Gideon J.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of York Heslington  York YO10 5DD UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3119-6731","authenticated-orcid":false,"given":"Neha S.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health School of Chemistry and Physics Queensland University of Technology  2 George St Brisbane QLD 4000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3306-2550","authenticated-orcid":false,"given":"Vito","family":"Ferro","sequence":"additional","affiliation":[{"name":"School of Chemistry &amp; Molecular Biosciences The University of Queensland  Brisbane Queensland 4072 Australia"},{"name":"Australian Infectious Diseases Research Centre The University of Queensland  Brisbane Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","unstructured":"I. 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