{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T14:34:53Z","timestamp":1759588493692,"version":"3.41.2"},"reference-count":35,"publisher":"Portland Press Ltd.","issue":"2","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":507,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4,27]]},"abstract":"<jats:p>HIV drug resistant mutations that render the current Highly Active Anti-Retroviral Therapy (HAART) cocktail drugs ineffective are increasingly reported. To study the mechanisms of these mutations in conferring drug resistance, we computationally analyzed 14 reverse transcriptase (RT) structures of HIV-1 on the following parameters: drug-binding pocket volume, allosteric effects caused by the mutations, and structural thermal stability. We constructed structural correlation-based networks of the mutant RT\u2013drug complexes and the analyses support the use of efavirenz (EFZ) as the first-line drug, given that cross-resistance is least likely to develop from EFZ-resistant mutations. On the other hand, rilpivirine (RPV)-resistant mutations showed the highest cross-resistance to the other non-nucleoside RT inhibitors. With significant drug cross-resistance associated with the known allosteric drug-binding site, there is a need to identify new allosteric druggable sites in the structure of RT. Through computational analyses, we found such a novel druggable pocket on the HIV-1 RT structure that is comparable with the original allosteric drug site, opening the possibility to the design of new inhibitors.<\/jats:p>","DOI":"10.1042\/bsr20171113","type":"journal-article","created":{"date-parts":[[2018,2,8]],"date-time":"2018-02-08T09:53:15Z","timestamp":1518083595000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A computational study for rational HIV-1 non-nucleoside reverse transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design"],"prefix":"10.1042","volume":"38","author":[{"given":"Ron\u00a0Zhi-Hui","family":"Chiang","sequence":"first","affiliation":[{"name":"Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), Singapore 138671"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel\u00a0Ken-En","family":"Gan","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), Singapore 138671"},{"name":"p53 Laboratory, Agency for Science, Technology, and Research (A*STAR), Singapore 138648"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chinh\u00a0Tran-To","family":"Su","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), Singapore 138671"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,3,5]]},"reference":[{"key":"2021111618503157800_B1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1177\/095632020401500302","article-title":"Clinical utility of current NNRTIs and perspectives of new agents in this class under development","volume":"15:","author":"Zhang","year":"2004","journal-title":"Antivir. Chem. Chemother."},{"key":"2021111618503157800_B2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nrc797","article-title":"AIDS-related malignancies","volume":"2","author":"Boshoff","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"2021111618503157800_B3","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.virusres.2008.01.002","article-title":"Mechanisms of inhibition of HIV replication by non-nucleoside reverse transciptase","volume":"134","author":"Sluis-Cremer","year":"2008","journal-title":"Virus Res."},{"key":"2021111618503157800_B4","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/343470a0","article-title":"Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives","volume":"343","author":"Pauwels","year":"1990","journal-title":"Nature"},{"key":"2021111618503157800_B5","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1016\/0006-291X(89)92756-3","article-title":"Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative","volume":"165","author":"Baba","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021111618503157800_B6","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.antiviral.2005.05.001","article-title":"Antiviral drug discovery and development where chemistry meets with biomedicine","volume":"67","author":"De Clercq","year":"2005","journal-title":"Antiviral Res."},{"key":"2021111618503157800_B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/0929867324666170705122851","article-title":"HIV-1 non-nucleoside reverse transcriptase inhibitors SAR and lead optimization using CoMFA and CoMSIA studies (1995-2016)","volume":"24","author":"Vanangamudi","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"2021111618503157800_B8","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1021\/jm00111a045","article-title":"Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones","volume":"34","author":"Hargrave","year":"1991","journal-title":"J. Med. Chem."},{"key":"2021111618503157800_B9","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.bpj.2010.11.004","article-title":"Allosteric suppression of HIV-1 reverse transcriptase structural dynamics upon inhibitor binding","volume":"100","author":"Seckler","year":"2011","journal-title":"Biophys. J."},{"key":"2021111618503157800_B10","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/S0969-2126(96)00091-3","article-title":"Structure of unliganded HIV-1 reverse transcriptase at 2.7 \u00c5 resolution implications of conformational changes for polymerization and inhibition mechanisms","volume":"4","author":"Hsiou","year":"1996","journal-title":"Structure"},{"key":"2021111618503157800_B11","doi-asserted-by":"publisher","first-page":"11687","DOI":"10.1093\/nar\/gku819","article-title":"Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble flourescence","volume":"42","author":"Schauer","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2021111618503157800_B12","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.pbiomolbio.2004.07.001","article-title":"Crystallography and the design of anti-AIDS drugs. Conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"88","author":"Das","year":"2005","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"2021111618503157800_B13","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.coviro.2013.03.012","article-title":"HIV-1 reverse transcriptase and antiviral drug resistance (part 1of 2)","volume":"3","author":"Das","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"2021111618503157800_B14","first-page":"132","article-title":"Update of the drug resistance mutations in HIV-1","volume":"24","author":"Wensing","year":"2017","journal-title":"Top. Antiviral. Med."},{"key":"2021111618503157800_B15","volume-title":"Consolidated guidelines on the use of Antiretroviral Drugs for Treating and Preventing HIV Infection: recommendations for a public health approach","author":"WHO","year":"2016","edition":"2nd edn."},{"key":"2021111618503157800_B16","volume-title":"Guidelines on the public health response to pretreatment HIV drug resistance","author":"WHO","year":"2017","edition":"2nd edn."},{"key":"2021111618503157800_B17","first-page":"5.6.1","article-title":"Comparative protein structure modeling using Modeller","volume-title":"Current Protocols in Bioinformatics","author":"Webb","year":"2014"},{"key":"2021111618503157800_B18","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22488","article-title":"Improved prediction of protein side-chain conformations with SCWRL4","author":"Krinov","year":"2009","journal-title":"Proteins"},{"key":"2021111618503157800_B19","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"volume-title":"Gephi: An Open Source Software for Exploring and Manipulating Networks","year":"2009","author":"Bastian","key":"2021111618503157800_B20"},{"key":"2021111618503157800_B21","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-168","article-title":"Fpocket: an open source platform for a ligand pocket detection","volume":"10","author":"Guilloux","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2021111618503157800_B22","doi-asserted-by":"publisher","first-page":"W266","DOI":"10.1093\/nar\/gkt460","article-title":"SPACER: Server for Predicting Allosteric Communication and Effects of Regulation","volume":"41","author":"Goncearenco","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2021111618503157800_B23","doi-asserted-by":"publisher","first-page":"e1003569","DOI":"10.1371\/journal.pcbi.1003569","article-title":"A coarse-graind elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations","volume":"10","author":"Frappier","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2021111618503157800_B24","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/978-1-4939-6637-0_9","article-title":"Applications of normal mode analysis methods in computational protein design","volume":"1529","author":"Frappier","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"2021111618503157800_B25","doi-asserted-by":"crossref","DOI":"10.1186\/s12859-015-0771-1","article-title":"AlloPred: prediction of allosteric pockets on proteins using normal mode perturbation analysis","volume":"16","author":"Greener","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"2021111618503157800_B26","doi-asserted-by":"publisher","first-page":"e1004678","DOI":"10.1186\/s12859-015-0771-1","article-title":"Structure-based statistical mechanical model accounts for the causality and energetics of allosteric communications","volume":"12","author":"Guarnera","year":"2016","journal-title":"PLoS Comput. Biol."},{"key":"2021111618503157800_B27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx430","article-title":"AlloSigMA: allosteric signalling and mutation analysis server","author":"Guarnera","year":"2017","journal-title":"Bioinformatics"},{"key":"2021111618503157800_B28","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1093\/bioinformatics\/btx430","article-title":"Structural analyses of 2015-updated drug-resistant mutations in HIV-1 protease: an implication of protease inhibitor cross-resistance","volume":"17","author":"Su","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"2021111618503157800_B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-016-1372-3","article-title":"Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance","author":"Su","year":"2017","journal-title":"J. Biomol. Struct. Dyn."},{"key":"2021111618503157800_B30","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1080\/07391102.2017.1417160","article-title":"HIV-1 reverse transcriptase and antiviral drug resistance (part 1 of 2)","volume":"3","author":"Das","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"2021111618503157800_B31","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1016\/j.coviro.2013.03.012","article-title":"Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase","volume":"15","author":"Ren","year":"2000","journal-title":"Structure"},{"key":"2021111618503157800_B32","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1016\/S0969-2126(00)00513-X","article-title":"Effect of mutations at position E138 in HIV-1 reverse transcriptase and their interactions with the M184I mutation on defining patterns of resistance to nonnucleoside reverse transcriptase inhibitors rilpivirine and etravirine","volume":"57","author":"Xu","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"2021111618503157800_B33","doi-asserted-by":"publisher","first-page":"16177","DOI":"10.1128\/AAC.00348-13","article-title":"Examining the role of the HIV-1 reverse transcriptase p51 subunit in positioning and hydrolysis of RNA\/DNA hybrids","volume":"288","author":"Chung","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2021111618503157800_B34","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1046\/j.1432-1327.1998.2510487.x","article-title":"p66\/p51 and p51\/p51 recombinant forms of reverse transcriptase from human immunodeficiency virus type 1\u2013interactions with primer tRNA(Lys3), initiation of cDNA synthesis, and effect of inhibitors","volume":"251","author":"Dufour","year":"1998","journal-title":"Eur. J. Biochem."},{"key":"2021111618503157800_B35","doi-asserted-by":"publisher","first-page":"e1328","DOI":"10.1002\/wcms.1328","article-title":"Integrative approaches in HIV-1 non-nucleoside reverse transcriptase inhibitor design","volume":"8","author":"Poongavanam","year":"2018","journal-title":"WIREs Comput. Mol. Sci."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20171113\/482797\/bsr-2017-1113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20171113\/482797\/bsr-2017-1113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T19:27:36Z","timestamp":1637090856000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/38\/2\/BSR20171113\/57175\/A-computational-study-for-rational-HIV-1-non"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,5]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,4,27]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20171113","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"type":"print","value":"0144-8463"},{"type":"electronic","value":"1573-4935"}],"subject":[],"published":{"date-parts":[[2018,3,5]]},"article-number":"BSR20171113"}}