{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:36:35Z","timestamp":1791236195448,"version":"4.1.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T00:00:00Z","timestamp":1453420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0147225","type":"journal-article","created":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T21:07:37Z","timestamp":1453496857000},"page":"e0147225","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":55,"title":["Ribonuclease H\/DNA Polymerase HIV-1 Reverse Transcriptase Dual Inhibitor: Mechanistic Studies on the Allosteric Mode of Action of Isatin-Based Compound RMNC6"],"prefix":"10.1371","volume":"11","author":[{"given":"Angela","family":"Corona","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Meleddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Distinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Masaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Maccioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Men\u00e9ndez-Arias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart F. J.","family":"Le Grice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Tramontano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2016,1,22]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1126\/science.6189183","article-title":"Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)","volume":"220","author":"F Barr\u00e9-Sinoussi","year":"1983","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1056\/NEJM198411153112006","article-title":"A pathogenic retrovirus (HTLV-III) linked to AIDS","volume":"311","author":"S Broder","year":"1984","journal-title":"N Engl J Med"},{"key":"ref3","first-page":"293","article-title":"Oncogenesis and AIDS","author":"O Schatz","year":"1990"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1021\/bi0486740","article-title":"Dissecting the effects of DNA polymerase and ribonuclease H inhibitor combinations on HIV-1 reverse-transcriptase activities","volume":"44","author":"C a Shaw-Reid","year":"2005","journal-title":"Biochemistry"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.virusres.2007.12.015","article-title":"Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase","volume":"134","author":"L Men\u00e9ndez-Arias","year":"2008","journal-title":"Virus Res"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"11157","DOI":"10.1074\/jbc.272.17.11157","article-title":"Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function","volume":"272","author":"C Palaniappan","year":"1997","journal-title":"J Biol Chem"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1073\/pnas.85.4.1218","article-title":"Expression of soluble, enzymatically active, human immunodeficiency virus reverse transcriptase in Escherichia coli and analysis of mutants","volume":"85","author":"A Hizi","year":"1988","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"10763","DOI":"10.1073\/pnas.89.22.10763","article-title":"Human immunodeficiency virus type 1 reverse transcriptase: spatial and temporal relationship between the polymerase and RNase H activities","volume":"89","author":"V Gopalakrishnan","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"7852","DOI":"10.1128\/JVI.02203-06","article-title":"Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3\u2019-azido-3&apos;-dideoxythymidine","volume":"81","author":"JH Brehm","year":"2007","journal-title":"J Virol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/jac\/dkn060","article-title":"The involvement of HIV-1 RNAse H in resistance to nucleoside analogues","volume":"61","author":"B Roquebert","year":"2008","journal-title":"J Antimicrob Chemother"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20130850","article-title":"Transient kinetic analyses of the ribonuclease H cleavage activity of HIV-1 reverse transcriptase in complex with efavirenz and\/or a \u03b2-thujaplicinol analogue","volume":"455","author":"BD Herman","year":"2013","journal-title":"Biochem J"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1093\/nar\/gkv077","article-title":"Effects of HIV-1 reverse transcriptase connection subdomain mutations on polypurine tract removal and initiation of (+)-strand DNA synthesis","volume":"43","author":"G Betancor","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1186\/1471-2334-14-407","article-title":"Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe","volume":"14","author":"D Frentz","year":"2014","journal-title":"BMC Infect Dis"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"586401","DOI":"10.1155\/2012\/586401","article-title":"HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions","volume":"2012","author":"F Esposito","year":"2012","journal-title":"Mol Biol Int"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.4155\/fmc.13.178","article-title":"Active site and allosteric inhibitors of the ribonuclease H activity of HIV reverse transcriptase","volume":"5","author":"A Corona","year":"2013","journal-title":"Futur Med Chem"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"445","DOI":"10.2217\/fvl.14.24","article-title":"Can the ever-promising target HIV reverse transcriptase-associated RNase H become a success story for drug development?","volume":"9","author":"A Corona","year":"2014","journal-title":"Future Virol"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1021\/jm501132s","article-title":"Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1, 3-diones: dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities","volume":"58","author":"SK V Vernekar","year":"2015","journal-title":"J Med Chem"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.2174\/1381612811319100009","article-title":"Molecular Aspects of the RT\/drug Interactions. Perspective of Dual Inhibitors","volume":"19","author":"S Distinto","year":"2013","journal-title":"Curr Pharm Des"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1021\/cb600303y","article-title":"HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site","volume":"1","author":"DM Himmel","year":"2006","journal-title":"ACS Chem Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1021\/ci200194w","article-title":"Identification of alternative binding sites for inhibitors of HIV-1 ribonuclease H through comparative analysis of virtual enrichment studies","volume":"51","author":"AK Felts","year":"2011","journal-title":"J Chem Inf Model"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1747-0285.2010.01052.x","article-title":"Interaction of HIV-1 reverse transcriptase ribonuclease H with an acylhydrazone inhibitor","volume":"77","author":"Q Gong","year":"2011","journal-title":"Chem Biol Drug Des"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1111\/cbdd.12010","article-title":"Structural basis of the allosteric inhibitor interaction on the HIV-1 reverse transcriptase RNase H domain","volume":"80","author":"MT Christen","year":"2012","journal-title":"Chem Biol Drug Des"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ejmech.2012.01.056","article-title":"Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach","volume":"50","author":"S Distinto","year":"2012","journal-title":"Eur J Med Chem"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ejmech.2015.02.032","article-title":"(3Z)-3-(2-[4-(aryl)-1, 3-thiazol-2-yl]hydrazin-1-ylidene)-2, 3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase","volume":"93","author":"R Meleddu","year":"2015","journal-title":"Eur J Med Chem"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/0076-6879(95)62015-X","article-title":"Purification and characterization of human immunodeficiency virus type 1 reverse transcriptase","volume":"262","author":"SF Le Grice","year":"1995","journal-title":"Methods Enzymol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jmb.2009.07.081","article-title":"Increased thermostability and fidelity of DNA synthesis of wild-type and mutant HIV-1 group O reverse transcriptases","volume":"392","author":"M Alvarez","year":"2009","journal-title":"J Mol Biol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"4601","DOI":"10.1093\/nar\/gkt109","article-title":"Altered error specificity of RNase H-deficient HIV-1 reverse transcriptases during DNA-dependent DNA synthesis","volume":"41","author":"M \u00c1lvarez","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1002\/cmdc.201402015","article-title":"Design, synthesis, and biological evaluation of 1, 3-diarylpropenones as dual inhibitors of HIV-1 reverse transcriptase","volume":"9","author":"R Meleddu","year":"2014","journal-title":"ChemMedChem"},{"key":"ref29","article-title":"From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors","author":"L Xu","year":"2015","journal-title":"J Microbiol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/S0076-6879(82)87028-6","article-title":"The Yonetani-Theorell graphical method for examining overlapping subsites of enzyme active centers","volume":"87","author":"T Yonetani","year":"1982","journal-title":"Methods Enzymol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1111\/j.1742-4658.2011.08057.x","article-title":"Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases","volume":"278","author":"F Esposito","year":"2011","journal-title":"FEBS J"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"6101","DOI":"10.1128\/AAC.03605-14","article-title":"Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives","volume":"58","author":"A Corona","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/978-1-60327-058-8_19","article-title":"Methods for protein characterization by mass spectrometry, thermal shift (ThermoFluor) assay, and multiangle or static light scattering","volume":"426","author":"JE Nettleship","year":"2008","journal-title":"Methods Mol Biol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1002\/(SICI)1096-987X(199604)17:5\/6<520::AID-JCC2>3.0.CO;2-W","article-title":"Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions","volume":"17","author":"TA Halgren","year":"1996","journal-title":"J Comput Chem"},{"key":"ref35","first-page":"103","article-title":"Tetrahedron Computer Methodology","volume":"1","author":"W Hasel","year":"1988","journal-title":"Tetrahedron Comput Methodol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"HM Berman","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nsb0495-293","article-title":"High resolution structures of HIV-1 RT from four RT-inhibitor complexes","volume":"2","author":"J Ren","year":"1995","journal-title":"Nat Struct Biol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1073\/pnas.0711209105","article-title":"High-resolution structures of HIV-1 reverse transcriptase\/TMC278 complexes: strategic flexibility explains potency against resistance mutations","volume":"105","author":"K Das","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"14316","DOI":"10.1074\/jbc.275.19.14316","article-title":"Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding","volume":"275","author":"J Ren","year":"2000","journal-title":"J Biol Chem"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1021\/jm101536x","article-title":"Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket","volume":"54","author":"K Das","year":"2011","journal-title":"J Med Chem"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"10548","DOI":"10.1073\/pnas.0404151101","article-title":"Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors","volume":"101","author":"JD Pata","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.str.2009.09.016","article-title":"Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site","volume":"17","author":"DM Himmel","year":"2009","journal-title":"Structure"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"6474","DOI":"10.1021\/jp003919d","article-title":"Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides \u2020","volume":"105","author":"GA Kaminski","year":"2001","journal-title":"J Phys Chem B"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/jcc.20222","article-title":"Importance of accurate charges in molecular docking: quantum mechanical\/molecular mechanical (QM\/MM) approach","volume":"26","author":"AE Cho","year":"2005","journal-title":"J Comput Chem"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models","volume":"33","author":"PA Kollman","year":"2000","journal-title":"Acc Chem Res"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.antiviral.2004.11.002","article-title":"6-[1-(4-Fluorophenyl)methyl-1H-pyrrol-2-yl)]-2, 4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro","volume":"65","author":"E Tramontano","year":"2005","journal-title":"Antiviral Res"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"5436","DOI":"10.1021\/jm400405z","article-title":"Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H","volume":"56","author":"T Masaoka","year":"2013","journal-title":"J Med Chem"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1177\/1087057106292746","article-title":"Universal screening methods and applications of ThermoFluor","volume":"11","author":"MD Cummings","year":"2006","journal-title":"J Biomol Screen"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1074\/jbc.M111.314781","article-title":"Mutagenesis of human immunodeficiency virus reverse transcriptase p51 subunit defines residues contributing to vinylogous urea inhibition of ribonuclease H activity","volume":"287","author":"S Chung","year":"2012","journal-title":"J Biol Chem"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"7625","DOI":"10.1128\/JVI.00353-10","article-title":"Structural basis for the inhibition of RNase H activity of HIV-1 reverse transcriptase by RNase H active site-directed inhibitors","volume":"84","author":"H-P Su","year":"2010","journal-title":"J Virol"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1006\/viro.1997.8748","article-title":"Characterization of the reverse transcriptase of a human immunodeficiency virus type 1 group O isolate","volume":"236","author":"ME Qui\u00f1ones-Mateu","year":"1997","journal-title":"Virology"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1093\/nar\/gki268","article-title":"Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones","volume":"33","author":"SR Budihas","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1021\/jm900854h","article-title":"Conformational landscape of the human immunodeficiency virus type 1 reverse transcriptase non-nucleoside inhibitor binding pocket: lessons for inhibitor design from a cluster analysis of many crystal structures","volume":"52","author":"KA Paris","year":"2009","journal-title":"J Med Chem"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"6320","DOI":"10.1073\/pnas.90.13.6320","article-title":"Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA","volume":"90","author":"A Jacobo-Molina","year":"1993","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"9515","DOI":"10.1073\/pnas.142123199","article-title":"Mutations in the RNase H domain of HIV-1 reverse transcriptase affect the initiation of DNA synthesis and the specificity of RNase H cleavage in vivo","volume":"99","author":"JG Julias","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"4856","DOI":"10.1021\/bi015970t","article-title":"Altering the RNase H primer grip of human immunodeficiency virus reverse transcriptase modifies cleavage specificity","volume":"41","author":"JW Rausch","year":"2002","journal-title":"Biochemistry"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0147225","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T22:57:20Z","timestamp":1718319440000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0147225"}},"subtitle":[],"editor":[{"given":"Chandravanu","family":"Dash","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,1,22]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,1,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0147225","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,22]]}}}