{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:23:35Z","timestamp":1760243015737,"version":"build-2065373602"},"reference-count":123,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T00:00:00Z","timestamp":1439856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variational quantitative binding\u2013conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process.<\/jats:p>","DOI":"10.3390\/ijms160819553","type":"journal-article","created":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T10:31:11Z","timestamp":1439893871000},"page":"19553-19601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Double Variational Binding\u2014(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV  Pyrimidine Ligands"],"prefix":"10.3390","volume":"16","author":[{"given":"Mihai","family":"Putz","sequence":"first","affiliation":[{"name":"Laboratory of Structural and Computational Physical-Chemistry for Nanosciences and QSAR, Biology-Chemistry Department, West University of Timisoara, Str. Pestalozzi No. 16,  300115 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoleta","family":"Duda\u0219","sequence":"additional","affiliation":[{"name":"Laboratory of Structural and Computational Physical-Chemistry for Nanosciences and QSAR, Biology-Chemistry Department, West University of Timisoara, Str. Pestalozzi No. 16,  300115 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Isvoran","sequence":"additional","affiliation":[{"name":"Environmental Advanced Researches Laboratories, Biology-Chemistry Department,  West University of Timisoara, Str. Pestalozzi No. 16, 300115 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1021\/cen-09235-cover","article-title":"Aiming for HIV\u2019s weak spot","volume":"9","author":"Halford","year":"2014","journal-title":"Chem. Eng. News"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/31405","article-title":"Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody","volume":"393","author":"Kwong","year":"1998","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.virol.2005.06.008","article-title":"Identification of N-phenyl-N\u2032-(2, 2, 6, 6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4","volume":"339","author":"Zhao","year":"2005","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10973","DOI":"10.1021\/bi061193r","article-title":"Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120","volume":"45","author":"Madani","year":"2006","journal-title":"Biochemistry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/cbdd.12075","article-title":"Optimization of CD4\/gp120 inhibitors by thermodynamic-guided alanine-scanning mutagenesis","volume":"81","author":"Liu","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1021\/ar4002735","article-title":"Structure-based design, synthesis and validation of CD4-mimetic small molecule inhibitors of HIV-1 entry: Conversion of a viral entry agonist to an antagonist","volume":"47","author":"Courter","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.1128\/JVI.00540-14","article-title":"CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies","volume":"88","author":"Madani","year":"2014","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1002\/jps.23476","article-title":"Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended-release formulation of an HIV-1 attachment inhibitor phosphate ester prodrug","volume":"102","author":"Brown","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_9","first-page":"95","article-title":"Pyrimidine derivates with biological activity in anti-HIV therapy. The SPECTRAL-DIAGONAL-SAR approach","volume":"6","author":"Putz","year":"2014","journal-title":"Int. J. Chem. Model."},{"key":"ref_10","first-page":"317","article-title":"The nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors in the treatment of HIV infections (AIDS)","volume":"67","year":"2012","journal-title":"Adv. Pharmacol."},{"key":"ref_11","first-page":"222","article-title":"Chapter fifteen\u2014Nucleosides and Nucleotides for the Treatment of Viral Diseases","volume":"Volume 49","author":"Desai","year":"2014","journal-title":"Annual Reports in Medicinal Chemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/187152108783954597","article-title":"Development of non-nucleoside reverse transcriptase inhibitors for anti-HIV therapy","volume":"7","author":"Sahlberg","year":"2008","journal-title":"Anti-Infect. Agents Med. Chem."},{"key":"ref_13","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":"Esposito","year":"2012","journal-title":"Mol. Biol. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7448\/IAS.16.1.18567","article-title":"Non-nucleoside reverse transcriptase inhibitors: A review on pharmacokinetics, pharmacodynamics, safety and tolerability","volume":"16","author":"Usach","year":"2013","journal-title":"J. Int. AIDS Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/jhet.987","article-title":"New efficient and flexible synthetic route to emivirine and its analogs","volume":"50","author":"Li","year":"2013","journal-title":"J. Heterocycl. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.antiviral.2013.06.021","article-title":"Assessment of topical microbicides to prevent HIV-1 transmission: Concepts, testing, lessons learned","volume":"99","author":"Friend","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1021\/jm0508890","article-title":"HIV integrase inhibitors with nucleobase scaffolds: Discovery of a highly potent anti-HIV agent","volume":"49","author":"Nair","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Patel, R.V., Keum, Y.S., and Park, S.W. (2014). Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase. Eur. J. Med. Chem.","DOI":"10.1002\/chin.201532296"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1016\/j.bmc.2014.07.036","article-title":"Design and discovery of 5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase","volume":"22","author":"Zhang","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4202","DOI":"10.1016\/j.bmc.2010.05.004","article-title":"Pharmacophore and structure\u2013activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase","volume":"18","author":"Wang","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1021\/ml1002162","article-title":"N-3 hydroxylation of pyrimidine-2,4-diones yields dual inhibitors of HIV reverse transcriptase and integrase","volume":"2","author":"Tang","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1016\/j.bmcl.2011.02.069","article-title":"6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase","volume":"21","author":"Tang","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_23","first-page":"75","article-title":"Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989\u20132009)","volume":"85","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.coviro.2013.03.012","article-title":"HIV-1 reverse transcriptase and antiviral drug resistance. Part 1","volume":"3","author":"Das","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ijantimicag.2008.10.010","article-title":"Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV","volume":"33","year":"2009","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1021\/jm900492g","article-title":"Twenty-six years of anti-HIV drug discovery: Where do we stand and where do we go?","volume":"53","author":"Mehellou","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-pharmtox-010510-100228","article-title":"A 40-year journey in search of selective antiviral chemotherapy","volume":"51","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1128\/AAC.06307-11","article-title":"Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives","volume":"56","author":"Ordonez","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1749-6632.2011.05972.x","article-title":"Raltegravir: The first HIV-1 integrasestrand transfer inhibitor in the HIV armamentarium","volume":"1222","author":"Nguyen","year":"2011","journal-title":"Ann. N. Y. Acad. Sci.,"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.coviro.2013.03.014","article-title":"HIV-1 reverse transcriptase and antiviral drug resistance. Part 2","volume":"3","author":"Das","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_31","first-page":"548","article-title":"HIV-1 Reverse Transcriptase Structures","volume":"Volume 2","author":"Lennarz","year":"2013","journal-title":"Encyclopedia of Biological Chemistry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1126\/science.1377403","article-title":"Crystal structure at 3.5 \u00c5 resolution of HIV-1 reverse transcriptase complexed with an inhibitor","volume":"256","author":"Kohlstaedt","year":"1992","journal-title":"Science"},{"key":"ref_33","first-page":"223","article-title":"12 the structure of HIV-1 reverse transcriptase","volume":"23","author":"Kohlstaedt","year":"1993","journal-title":"Cold Spring Harb. Monogr. Arch."},{"key":"ref_34","doi-asserted-by":"crossref","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":"ref_35","first-page":"171","article-title":"An overview on HIV-1 reverse transcriptase inhibitors","volume":"3","author":"Ravichandran","year":"2008","journal-title":"Dig. J. Nanomater. Biostruct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.jmb.2008.10.071","article-title":"Structure and function of HIV-1 reverse transcriptase: Molecular mechanisms of polymerization and inhibition","volume":"385","author":"Sarafianos","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6593","DOI":"10.1016\/j.bmcl.2013.10.059","article-title":"Novel piperidinylamino-diarylpyrimidine derivatives with dual structural conformations as potent HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"23","author":"Chen","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1110\/ps.072829007","article-title":"Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses","volume":"16","author":"Xia","year":"2007","journal-title":"Protein Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19501","DOI":"10.1021\/ja3092642","article-title":"Crystal structures of HIV-1 reverse transcriptase with picomolar inhibitors reveal key interactions for drug design","volume":"134","author":"Frey","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/j.bmcl.2011.12.132","article-title":"Discovery of dimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase","volume":"22","author":"Ekkati","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_41","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":"Paris","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nsb0495-293","article-title":"High resolution structures of HIV-1 RT from four RT\u2013inhibitor complexes","volume":"2","author":"Ren","year":"1995","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/nsb0495-303","article-title":"Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors","volume":"2","author":"Esnouf","year":"1995","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1126\/science.1163108","article-title":"Slide into action: Dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates","volume":"322","author":"Liu","year":"2008","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1124\/mol.107.038596","article-title":"Efavirenz accelerates HIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision","volume":"73","author":"Radzio","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.virusres.2008.01.002","article-title":"Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors","volume":"134","author":"Tachedjian","year":"2008","journal-title":"Virus Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14410","DOI":"10.1073\/pnas.222366699","article-title":"Structure of HIV-2 reverse transcriptase at 2.35-\u00c5 resolution and the mechanism of resistance to non-nucleoside inhibitors","volume":"99","author":"Ren","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1248\/cpb.54.325","article-title":"Synthesis and anti-HIV-1 and anti-HCMV activity of 1-substituted 3-(3, 5-dimethylbenzyl) uracil derivatives","volume":"54","author":"Maruyama","year":"2006","journal-title":"Chem. Pharm. Bull."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8390","DOI":"10.1128\/JVI.74.18.8390-8401.2000","article-title":"Mutants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase resistant to nonnucleoside reverse transcriptase inhibitors demonstrate altered rates of RNase H cleavage that correlate with HIV-1 replication fitness in cell culture","volume":"74","author":"Archer","year":"2000","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.ejmech.2014.05.059","article-title":"Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors","volume":"82","author":"Meng","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1128\/JVI.01154-07","article-title":"Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors","volume":"82","author":"Hachiya","year":"2008","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5238","DOI":"10.1128\/JVI.01545-09","article-title":"A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors","volume":"84","author":"Nikolenko","year":"2010","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.2174\/092986708784221467","article-title":"The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection","volume":"15","author":"Martins","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"359","DOI":"10.2174\/092986711794839142","article-title":"Recent advances in DAPYs and related analogues as HIV-1 NNRTIs","volume":"18","author":"Chen","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejmech.2014.09.054","article-title":"Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization","volume":"87","author":"Liu","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","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":"ref_57","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1021\/jm00132a002","article-title":"A novel lead for specific anti-HIV-1 agents: 1-[(2-Hydroxyethoxy) methyl]-6-(phenylthio) thymine","volume":"32","author":"Miyasaka","year":"1989","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","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":"ref_59","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/1743-422X-8-230","article-title":"Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors","volume":"8","author":"Huang","year":"2011","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1021\/jm201506e","article-title":"Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl\/alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile","volume":"55","author":"Wang","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1128\/AAC.00972-07","article-title":"Comparative evaluation of the inhibitory activities of a series of pyrimidinedione congeners that inhibit human immunodeficiency virus types 1 and 2","volume":"52","author":"Buckheit","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5243","DOI":"10.1128\/AAC.05237-11","article-title":"Development of dual-acting pyrimidinediones as novel and highly potent topical anti-HIV microbicides","volume":"55","author":"Buckheit","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.antiviral.2011.10.013","article-title":"Antiviral interactions of combinations of highly potent 2,4 (1H, 3H)-pyrimidinedione congeners and other anti-HIV agents","volume":"92","author":"Hartman","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1007\/s11095-012-0715-7","article-title":"Vaginal film drug delivery of the pyrimidinedione IQP-0528 for the prevention of HIV infection","volume":"29","author":"Ham","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e75306","DOI":"10.1371\/journal.pone.0075306","article-title":"In vitro and ex vivo evaluations on transdermal delivery of the HIV inhibitor IQP-0410","volume":"8","author":"Ham","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1128\/AAC.01368-10","article-title":"Vaginal microbicide gel for delivery of IQP-0528, a pyrimidinedione analog with a dual mechanism of action against HIV-1","volume":"55","author":"Mahalingam","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1016\/j.bmc.2011.07.023","article-title":"Synthesis and structure\u2013activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs","volume":"19","author":"Gu","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1016\/j.bmc.2010.03.007","article-title":"Synthesis and biological evaluation of 4-(hydroxyimino) arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV","volume":"18","author":"Feng","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ejmech.2012.04.004","article-title":"Chiral resolution, absolute configuration assignment and biological activity of racemic diarylpyrimidine CH(OH)-DAPY as potent non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"53","author":"Gu","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1016\/j.bmc.2014.02.030","article-title":"Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"22","author":"Yan","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/cmdc.200800334","article-title":"Structural modifications of DAPY analogues with potent anti-HIV-1 activity","volume":"4","author":"Feng","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.ejmech.2013.04.052","article-title":"Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"65","author":"Yang","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/cmdc.201000045","article-title":"Lead optimization of diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase","volume":"5","author":"Zeng","year":"2010","journal-title":"ChemMedChem"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1016\/j.bmc.2011.10.002","article-title":"Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines (CAPYs) as HIV-1 NNRTIs","volume":"19","author":"Gu","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/jac\/dki464","article-title":"Dawn of non-nucleoside inhibitor-based anti-HIV microbicides","volume":"57","author":"Uckun","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1002\/cmdc.201200056","article-title":"Synthesis, biological activity, and ADME properties of novel S-DABOs\/N-DABOs as HIV reverse transcriptase inhibitors","volume":"7","author":"Radi","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1021\/jm101626c","article-title":"Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: New, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level","volume":"54","author":"Rotili","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"152","DOI":"10.2174\/092986712803414169","article-title":"Dihydro-alkoxyl-benzyl-oxopyrimidine derivatives (DABOs) as non-nucleoside reverse transcriptase inhibitors: An update review (2001\u20132011)","volume":"19","author":"Yang","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6477","DOI":"10.1016\/j.bmc.2013.08.040","article-title":"Towards new C6-rigid S-DABO HIV-1 reverse transcriptase inhibitors: Synthesis, biological investigation and molecular modeling studies","volume":"21","author":"Wu","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.ejmech.2008.06.028","article-title":"Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethyl-substituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"44","author":"Wang","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1016\/j.bmc.2010.03.025","article-title":"Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"18","author":"Qin","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1016\/j.bmcl.2009.04.051","article-title":"Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"20","author":"Qin","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7104","DOI":"10.3390\/molecules19067104","article-title":"Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodine-6-substituted-benzyl-pyrimidine-4 (3H)-ones as potent HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"19","author":"Zhang","year":"2014","journal-title":"Molecules"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"8582","DOI":"10.1021\/jm201134m","article-title":"Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents","volume":"54","author":"Bollini","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1021\/jm501908a","article-title":"Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants","volume":"58","author":"Frey","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7398","DOI":"10.1016\/j.bmc.2013.09.051","article-title":"Design, synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs","volume":"21","author":"Rai","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1177\/095632020301400506","article-title":"Synthesis and antiviral activity of 1,3-disubstituted uracils against HIV-1 and HCMV","volume":"14","author":"Maruyama","year":"2003","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/nass\/48.1.3","article-title":"Synthesis and Antiviral Activity of 1-Substituted 3-(3, 5-dimethylbenzyl) Uracil against HIV-1","volume":"Volume 48","author":"Maruyama","year":"2004","journal-title":"Nucleic Acids Symposium Series"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3851\/IMP1844","article-title":"Synthesis of 1-benzyl-3-(3, 5-dimethylbenzyl) uracil derivatives with potential anti-HIV activity","volume":"22","author":"Isono","year":"2011","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5900","DOI":"10.1016\/j.bmc.2013.06.061","article-title":"Synthesis and evaluation of novel 3-(3, 5-dimethylbenzyl) uracil analogs as potential anti-HIV-1 agents","volume":"21","author":"Sakakibara","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/2040206614566584","article-title":"Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3, 5-dimethylbenzyl) uracil and N-3, 5-dimethylbenzyl-substituted urea derivatives","volume":"24","author":"Sakakibara","year":"2015","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8310","DOI":"10.1016\/j.bmc.2010.09.070","article-title":"1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents","volume":"18","author":"Novikov","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5794","DOI":"10.1016\/j.bmc.2011.08.025","article-title":"1-[2-(2-Benzoyl-and 2-benzylphenoxy) ethyl] uracils as potent anti-HIV-1 agents","volume":"19","author":"Novikov","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.bmc.2012.12.027","article-title":"N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase","volume":"21","author":"Novikov","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1039\/c3md00225j","article-title":"Structure-activity evaluation of new uracil-based non-nucleoside inhibitors of HIV reverse transcriptase","volume":"4","author":"Matyugina","year":"2013","journal-title":"MedChemComm"},{"key":"ref_96","unstructured":"Chemical Identifier Resolver beta 4. Available online: http:\/\/cactus.nci.nih.gov\/chemical\/structure."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1007\/s11224-013-0249-6","article-title":"Variational principles for mechanistic quantitative structure\u2013activity relationship (QSAR) studies: Application on uracil derivatives\u2019 anti-HIV action","volume":"24","author":"Putz","year":"2013","journal-title":"Struct. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9061","DOI":"10.3390\/molecules18089061","article-title":"Determining chemical reactivity driving biological activity from SMILES transformations: The bonding mechanism of anti-HIV pyrimidines","volume":"18","author":"Putz","year":"2013","journal-title":"Molecules"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Putz, M.V. (2015). Quantum Nanochemistry. A Fully Integrated Approach: Vol V. Quantum Structure-Activity Relationship (Qu-SAR), Apple Academic Press & CRC Press.","DOI":"10.1201\/b21418"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7205","DOI":"10.1016\/j.tetlet.2009.10.044","article-title":"Spiroheterocyclic compounds: Old stories with new outcomes","volume":"50","author":"Moldoveanu","year":"2009","journal-title":"Tetrahedron Lett."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"12520","DOI":"10.1128\/JVI.01528-08","article-title":"Mechanism of antiviral drug resistance of Vaccinia virus: Identification of residues in the viral DNA polymerase conferring differential resistance to antipoxvirus drugs","volume":"82","author":"Gammon","year":"2008","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.bmc.2008.11.061","article-title":"Synthesis and evaluation of novel chloropyridazine derivatives as potent human rhinovirus (HRV) capsid-binding inhibitors","volume":"17","author":"Fan","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1021\/jm040158k","article-title":"New approaches toward anti-HIV chemotherapy","volume":"48","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.2174\/092986707780597952","article-title":"Current developments in the synthesis and biological activity of HIV-1 double-drug inhibitors","volume":"14","author":"Muhanji","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1002\/jhet.5570440528","article-title":"Pyridazine and phthalazine derivatives with potential antimicrobial activity","volume":"44","author":"Butnariu","year":"2007","journal-title":"J. Heterocycl. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1016\/j.bmc.2009.02.028","article-title":"New pyridazine derivatives: Synthesis, chemistry and biological activity","volume":"17","author":"Butnariu","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1016\/j.ejmech.2008.06.017","article-title":"Diazinium salts with dihydroxyacetophenone skeleton: Syntheses and antimicrobial activity","volume":"44","author":"Balan","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"12577","DOI":"10.1021\/jo402149f","article-title":"Atropisomerization in N-aryl-2(1H)-pyrimidin-(thi) ones: A ring-opening\/rotation\/ring-closure process in place of a classical rotation around the pivot bond","volume":"78","author":"Najahi","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1002\/jcc.23576","article-title":"QSARINS-Chem: Insubria datasets and new QSAR\/QSPR models for environmental pollutants in QSARINS","volume":"35","author":"Gramatica","year":"2014","journal-title":"J. Comp. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_111","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":"Das","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1046\/j.1432-1327.2002.02811.x","article-title":"Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant","volume":"269","author":"Lindberg","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comp. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"W363","DOI":"10.1093\/nar\/gki481","article-title":"PatchDock and SymmDock: Servers for rigid and symmetric docking","volume":"33","author":"Inbar","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comp. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/prot.21495","article-title":"FireDock: Fast interaction refinement in molecular docking","volume":"69","author":"Andrusier","year":"2007","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"55","DOI":"10.6026\/97320630005055","article-title":"ContPro: A web tool for calculating amino acid contact distances in protein from 3D\u2013structure at different distance threshold","volume":"5","author":"Firoz","year":"2010","journal-title":"Bioinformation"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.bmc.2014.12.059","article-title":"Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors","volume":"23","author":"Wang","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1007\/s00894-011-1236-8","article-title":"Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors","volume":"18","author":"Mao","year":"2012","journal-title":"J. Mol. Model."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1021\/jm1002233","article-title":"Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): Implications for drug design","volume":"53","author":"Lansdon","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1758-2652-14-4","article-title":"Finding a cure for HIV: Will it ever be achievable?","volume":"24","author":"Lewin","year":"2011","journal-title":"J. Int. AIDS Soc."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1097\/QAD.0b013e328353f3f1","article-title":"HIV reservoirs: Pathogenesis and obstacles to viral eradication and cure","volume":"26","author":"Chun","year":"2012","journal-title":"AIDS"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1758-2652-15-16","article-title":"Controversies in HIV cure research","volume":"15","author":"Johnston","year":"2012","journal-title":"J. Int. AIDS Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/8\/19553\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:46:56Z","timestamp":1760215616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/8\/19553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,18]]},"references-count":123,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2015,8]]}},"alternative-id":["ijms160819553"],"URL":"https:\/\/doi.org\/10.3390\/ijms160819553","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2015,8,18]]}}}