{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:08:29Z","timestamp":1788354509871,"version":"build-2803163510"},"reference-count":24,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,7,26]],"date-time":"2018-07-26T00:00:00Z","timestamp":1532563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GMO69832"],"award-info":[{"award-number":["R01 GMO69832"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Informatics"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>HIV\u20101 protease (HIV\u2010PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error\u2010prone of HIV reverse transcriptase, mutations in HIV\u2010PR often occur, inducing drug\u2010resistance to inhibitors. Some HIV\u2010PR mutations can make the flaps of the enzyme more flexible thus increasing the flaps opening rate and inhibitor releasing. It has been shown that by targeting novel binding sites on HIV\u2010PR with small molecules, it is possible to alter the equilibrium of flap conformational states. A previous fragment\u2010based crystallographic screen have found two novel binding sites for small fragments in the inhibited, closed form of HIV\u2010PR, termed flap and exo sites. While these experiments were performed in wild type HIV\u2010PR, it still remains to be proven whether these small fragments can stabilize the closed conformation of flaps in resistant forms of the enzyme. Here we performed Molecular Dynamics simulations of wild type and mutant form of HIV\u2010PR bound to inhibitor TL\u20103. Simulations show that on going from wild type to 6X mutant the equilibrium shifts from closed to semi\u2010open conformation of flaps. However, when fragment Br6 is placed at flap site of mutant form, the enzyme is restored back to closed conformation. This finding supports the hypothesis that allosteric inhibitors, together with active site inhibitors could increase the number of point mutations necessary for appreciable clinical resistance to AIDS therapy.<\/jats:p>","DOI":"10.1002\/minf.201800053","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T06:54:02Z","timestamp":1532674442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Flap\u2010site Fragment Restores Back Wild\u2010type Behaviour in Resistant Form of HIV Protease"],"prefix":"10.1002","volume":"37","author":[{"given":"Adriano","family":"Luchi","sequence":"first","affiliation":[{"name":"Lab. 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Libertad 5470 Corrientes 3400 Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Forli","sequence":"additional","affiliation":[{"name":"Molecular Graphics Lab Department of Integrative Structural and Computational Biology, MB-112, the Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037-1000"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Olson","sequence":"additional","affiliation":[{"name":"Molecular Graphics Lab Department of Integrative Structural and Computational Biology, MB-112, the Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037-1000"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e9lida","family":"Peruchena","sequence":"additional","affiliation":[{"name":"Lab. Estructura Molecular y Propiedades, IQUIBA-NEA Universidad Nacional del Nordeste, CONICET, FACENA Av. 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