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Currently, of the approximately 6000 known conotoxin sequences, only about 3% have associated structural characterization, which leads to a bottleneck in rapid high-throughput screening (HTS) for identification of potential leads or threats. In this work, we combine a graph-based approach with homology modeling to expand the library of conotoxin structures and to identify those conotoxin sequences that are of the greatest value for experimental structural characterization. The latter would allow for the rapid expansion of the known structural space for generating high quality template-based models. Our approach generalizes to other evolutionarily-related, short, cysteine-rich venoms of interest. Overall, we present and validate an approach for venom structure modeling and experimental guidance and employ it to produce a 290%-larger library of approximate conotoxin structures for HTS. We also provide a set of ranked conotoxin sequences for experimental structure determination to further expand this library.<\/jats:p>","DOI":"10.3390\/md18050256","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T10:27:19Z","timestamp":1589452039000},"page":"256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Graph-Directed Approach for Downselecting Toxins for Experimental Structure Determination"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6738-1261","authenticated-orcid":false,"given":"Rachael A.","family":"Mansbach","sequence":"first","affiliation":[{"name":"Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7155-2764","authenticated-orcid":false,"given":"Srirupa","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"},{"name":"Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-3844","authenticated-orcid":false,"given":"Timothy","family":"Travers","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"},{"name":"Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9368-3044","authenticated-orcid":false,"given":"S.","family":"Gnanakaran","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.phrs.2016.01.009","article-title":"Harnessing the knowledge of animal toxins to generate drugs","volume":"112","author":"Zambelli","year":"2016","journal-title":"Pharmacol. 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