Raghuraman, Arjun Mosier, Philip D. Desai, Umesh R. Finding a Needle in a Haystack:  Development of a Combinatorial Virtual Screening Approach for Identifying High Specificity Heparin/Heparan Sulfate Sequence(s) We describe a combinatorial virtual screening approach for predicting high specificity heparin/heparan sulfate sequences using the well-studied antithrombin−heparin interaction as a test case. Heparan sulfate hexasaccharides were simulated in the ‘average backbone' conformation, wherein the inter-glycosidic bond angles were held constant at the mean of the known solution values, irrespective of their sequence. Molecular docking utilized GOLD with restrained inter-glycosidic torsions and intra-ring conformations, but flexible substituents at the 2-, 3-, and 6-positions and explicit incorporation of conformational variability of the iduronate residues. The approach reproduces the binding geometry of the sequence-specific heparin pentasaccharide to within 2.5 Å. Screening of a combinatorial virtual library of 6859 heparin hexasaccharides using a dual filter strategy, in which predicted antithrombin affinity was the first filter and self-consistency of docking was the second, resulted in only 10 sequences. Of these, nine were found to bind antithrombin in a manner identical to the natural pentasaccharide, while a novel hexasaccharide bound the inhibitor in a unique but dramatically different geometry and orientation. This work presents the first approach on combinatorial library screening for heparin/heparan sulfate GAGs to determine high specificity sequences and opens up huge opportunities to investigate numerous other physiologically relevant GAG−protein interactions. solution values;2.5 Å. Screening;screening approach;GAG;specificity sequences;iduronate residues;Heparan sulfate hexasaccharides;filter strategy;bind antithrombin;conformation;interaction;test case;Molecular docking;6859 heparin hexasaccharides;binding geometry;antithrombin affinity;pentasaccharide;combinatorial library screening;10 sequences;novel hexasaccharide;Combinatorial Virtual Screening Approach 2006-06-15
    https://acs.figshare.com/articles/dataset/Finding_a_Needle_in_a_Haystack_Development_of_a_Combinatorial_Virtual_Screening_Approach_for_Identifying_High_Specificity_Heparin_Heparan_Sulfate_Sequence_s_/3075658
10.1021/jm060092o.s001