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Previously, a model was created for an allosteric site located between the flap and the core of HIV-1p, called the Eye site (Biopolymers2008, 89, 643\u2212652.). Here, results from our first study were combined with a ligand-based, lead-hopping method to identify a novel compound (NIT). NIT inhibits HIV-1p, independent of the presence of an active-site inhibitor such as pepstatin A. Assays showed that NIT acts on an allosteric site other than the dimerization interface. MD simulations of the ligand\u2013protein complex show that NIT stably binds in the Eye site and restricts the flaps. That bound state of NIT is consistent with a crystal structure of similar fragments bound in the Eye site ( Chem. Biol. Drug Des.2010, 75, 257\u2212268.). Most importantly, NIT is equally potent against wild-type and a multidrug-resistant mutant of HIV-1p, which highlights the promise of allosteric inhibitors circumventing existing clinical resistance.<\/jats:p>","DOI":"10.1021\/jm5008352","type":"journal-article","created":{"date-parts":[[2014,7,25]],"date-time":"2014-07-25T11:27:52Z","timestamp":1406287672000},"page":"6468-6478","source":"Crossref","is-referenced-by-count":25,"title":["An Allosteric Modulator of HIV-1 Protease Shows Equipotent Inhibition of Wild-Type and Drug-Resistant Proteases"],"prefix":"10.1021","volume":"57","author":[{"given":"Peter M.-U.","family":"Ung","sequence":"first","affiliation":[{"name":"University of Michigan , , 428 Church Street , , ,","place":["Ann Arbor, Michigan, United States, 48109-1065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"James B.","family":"Dunbar","sequence":"additional","affiliation":[{"name":"University of Michigan , , 428 Church Street , , ,","place":["Ann Arbor, Michigan, United States, 48109-1065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Gestwicki","sequence":"additional","affiliation":[{"name":"University of Michigan , , 210 Washtenaw Avenue , , ,","place":["Ann Arbor, Michigan, United States, 48109-2216"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Carlson","sequence":"additional","affiliation":[{"name":"University of Michigan , , 428 Church Street , , ,","place":["Ann Arbor, Michigan, United States, 48109-1065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,7,25]]},"reference":[{"key":"2026090201205631100_cit1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/bip.20993","article-title":"A Poke in the Eye: Inhibiting HIV-1\nProtease through Its Flap-Recognition Pocket","volume":"89","author":"Damm","year":"2008","journal-title":"Biopolymers"},{"key":"2026090201205631100_cit2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1747-0285.2009.00943.x","article-title":"Fragment-Based Screen Against HIV\nProtease","volume":"75","author":"Perryman","year":"2010","journal-title":"Chem. 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