{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:39:19Z","timestamp":1760243959734,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T00:00:00Z","timestamp":1291161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI &gt; FRV &gt; FRT &gt; FHV &gt; FRS &gt; FRG &gt; YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH3+) and C-terminus (COO\u2212) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N-terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.<\/jats:p>","DOI":"10.3390\/ijms11124932","type":"journal-article","created":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T11:17:07Z","timestamp":1291202227000},"page":"4932-4951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6969-8177","authenticated-orcid":false,"given":"Zhiwei","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China"},{"name":"Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuangang","family":"Zu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujie","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2010,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/303041a0","article-title":"Structure of the catalytic and antigenic sites in influenza virus neuraminidase","volume":"303","author":"Colman","year":"1983","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/nrd2400","article-title":"The war against influenza: discovery and development of sialidase inhibitors","volume":"6","year":"2007","journal-title":"Nat. Rev. Drug. Discov"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/nature08260","article-title":"In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses","volume":"460","author":"Itoh","year":"2009","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev.med.59.061506.213121","article-title":"Medical management of influenza infection","volume":"59","author":"Moscona","year":"2008","journal-title":"Annu. Rev. Med"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJMra050740","article-title":"Neuraminidase inhibitors for influenza","volume":"353","author":"Moscona","year":"2005","journal-title":"N. Engl. J. Med"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"i5","DOI":"10.1093\/jac\/dki018","article-title":"Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic","volume":"55","author":"Ward","year":"2005","journal-title":"J. Antimicrob. Chemother"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.antiviral.2008.01.003","article-title":"Current and future antiviral therapy of severe seasonal and avian influenza","volume":"78","author":"Beigel","year":"2008","journal-title":"Antivir. Res"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.virusres.2004.02.034","article-title":"Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors","volume":"103","author":"Gubareva","year":"2004","journal-title":"Virus Res"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1056\/NEJMoa054512","article-title":"Oseltamivir resistance during treatment of influenza A (H5N1) infection","volume":"353","author":"Tran","year":"2005","journal-title":"N. Engl. J. Med"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1056\/NEJMra1000449","article-title":"Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection","volume":"362","author":"Bautista","year":"2010","journal-title":"N. Engl. J. Med"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.tips.2007.04.005","article-title":"Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention","volume":"28","author":"Neyts","year":"2007","journal-title":"Trends Pharmacol. Sci"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2174\/1389450043490604","article-title":"Controlling influenza by inhibiting the virus\u2019s neuraminidase","volume":"5","author":"Garman","year":"2004","journal-title":"Curr. Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature05114","article-title":"The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design","volume":"443","author":"Russell","year":"2006","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1529\/biophysj.106.092528","article-title":"On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9","volume":"92","author":"Aruksakunwong","year":"2007","journal-title":"Biophys. J"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nsmb.1779","article-title":"Structures of influenza A proteins and insights into antiviral drug targets","volume":"17","author":"Das","year":"2010","journal-title":"Nat. Struct. Mol. Biol"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/pro.5560040606","article-title":"Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase","volume":"4","author":"Varghese","year":"1995","journal-title":"Protein Sci"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0969-2126(98)00075-6","article-title":"Drug design against a shifting target: A structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase","volume":"6","author":"Varghese","year":"1998","journal-title":"Structure"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1110\/ps.41801","article-title":"Analysis of inhibitor binding in influenza virus neuraminidase","volume":"10","author":"Smith","year":"2001","journal-title":"Protein Sci"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1021\/jm010528u","article-title":"Structural Studies of the Resistance of Influenza Virus Neuramindase to Inhibitors","volume":"45","author":"Smith","year":"2002","journal-title":"J. Med. Chem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/363418a0","article-title":"Rational design of potent sialidase-based inhibitors of influenza virus replication","volume":"363","author":"Wu","year":"1993","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1021\/ja963036t","article-title":"Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity","volume":"119","author":"Kim","year":"1997","journal-title":"J. Am. Chem. Soc"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1128\/JVI.01678-06","article-title":"Inhibition of influenza virus infection by a novel antiviral peptide that targets viral attachment to cells","volume":"80","author":"Jones","year":"2006","journal-title":"J. Virol"},{"key":"ref_23","first-page":"165","article-title":"Screening of peptides as broad-spectrum neuraminidase inhibitors against influenza viruses","volume":"23","author":"Kuang","year":"2007","journal-title":"Chin. J. Virol"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1021\/jm801570y","article-title":"Inhibition of influenza virus infections by sialylgalactose-binding peptides selected from a phage library","volume":"52","author":"Matsubara","year":"2009","journal-title":"J. Med. Chem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1743-422X-6-74","article-title":"Identification and characterisation of a novel anti-viral peptide against avian influenza virus H9N2","volume":"6","author":"Rajik","year":"2009","journal-title":"Virol. J"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nrd1133","article-title":"Large-scale manufacture of peptide therapeutics by chemical synthesis","volume":"2","author":"Bray","year":"2003","journal-title":"Nat. Rev. Drug Discov"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nrd1424","article-title":"Building blocks for peptide drugs","volume":"3","author":"Owens","year":"2004","journal-title":"Nat. Rev. Drug Discov"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S1359-6446(04)03123-X","article-title":"Antimicrobial peptides as carriers of drugs","volume":"9","author":"Rappocciolo","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nbt1190","article-title":"Screening for peptide drugs from the natural repertoire of biodiverse protein folds","volume":"24","author":"Watt","year":"2006","journal-title":"Nat. Biotechnol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1126\/science.1165265","article-title":"Antimicrobial defense and persistent infection in insects","volume":"322","author":"Haine","year":"2008","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11588","DOI":"10.1128\/JVI.79.18.11588-11597.2005","article-title":"Herpes simplex virus glycoprotein B binds to cell surfaces independently of heparan sulfate and blocks virus entry","volume":"79","author":"Bender","year":"2005","journal-title":"J. Virol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0753-3322(03)00043-X","article-title":"The importance of glutathione in human disease","volume":"57","author":"Townsend","year":"2003","journal-title":"Biomed. Pharmacother"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2174\/1568006013338123","article-title":"Development and current applications of thrombin-specific inhibitors","volume":"1","author":"Shen","year":"2001","journal-title":"Curr. Drug Targets Cardiovasc. Haematol. Disord"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/(SICI)1097-0282(1996)40:2<235::AID-BIP3>3.0.CO;2-X","article-title":"Design and synthesis of substrate-based peptidomimetic human immunodeficiency virus protease inhibitors containing the hydroxymethylcarbonyl isostere","volume":"40","author":"Kiso","year":"1996","journal-title":"Biopolymers"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1021\/ar700109k","article-title":"Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection","volume":"41","author":"Njoroge","year":"2008","journal-title":"Acc. Chem. Res"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1749-6632.2003.tb03172.x","article-title":"New insights into the functions of alpha-MSH and related peptides in the immune system","volume":"994","author":"Luger","year":"2003","journal-title":"Ann. N.Y. Acad. Sci"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10035","DOI":"10.1039\/b909299d","article-title":"The conformational analysis and proton transfer of the neuraminidase inhibitors: a theoretical study","volume":"11","author":"Yang","year":"2009","journal-title":"Phys. Chem. Chem. Phys"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.jtbi.2010.08.029","article-title":"Synergistic effects in the designs of neuraminidase ligands: Analysis from docking and molecular dynamics studies","volume":"267","author":"Yang","year":"2010","journal-title":"J. Theor. Biol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5628","DOI":"10.1021\/jm030060q","article-title":"Investigation of Neuraminidase-Substrate Recognition Using Molecular Dynamics and Free Energy Calculations","volume":"46","author":"Masukawa","year":"2003","journal-title":"J. Med. Chem"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1110\/ps.03129704","article-title":"Molecular dynamics and free energy analysis of neuraminidase-ligand interactions","volume":"13","author":"Bonnet","year":"2004","journal-title":"Protein Sci"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jmgm.2005.06.003","article-title":"Scoring binding affinity of multiple ligands using implicit solvent and a single molecular dynamics trajectory: Application to Influenza neuraminidase","volume":"24","author":"Bonnet","year":"2005","journal-title":"J. Mol. Graph. Model"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1021\/bi0205449","article-title":"Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series","volume":"42","author":"Stoll","year":"2003","journal-title":"Biochemistry"},{"key":"ref_43","first-page":"97","article-title":"The calcium ion and conserved water molecules in neuraminidases: roles and implications for substrate binding","volume":"7","author":"Yang","year":"2008","journal-title":"Internet. Electron. J. Mol. Des"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4702","DOI":"10.1021\/ja8085643","article-title":"Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations","volume":"131","author":"Amaro","year":"2009","journal-title":"J. Am. Chem. Soc"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1002\/pro.5560031007","article-title":"Influenza virus neuraminidase: structure, antibodies, and inhibitors","volume":"3","author":"Colman","year":"1994","journal-title":"Protein Sci"},{"key":"ref_46","first-page":"1370","article-title":"A computational investigation on the interaction mechanisms of neuraminidases and 3-(3-pentyloxy)benzoic acid","volume":"14","author":"Yang","year":"2010","journal-title":"Acta. Chimica. Sinica"},{"key":"ref_47","unstructured":"(2005). InisghtII, 2005, Accelrys Inc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5142","DOI":"10.1021\/jm990105g","article-title":"Binding constants of neuraminidase inhibitors: An investigation of the linear interaction energy method","volume":"42","author":"Wall","year":"1999","journal-title":"J. Med. Chem"},{"key":"ref_49","unstructured":"Frisch, MJ, Trucks, GW, Schlegel, HB, Scuseria, GE, Robb, MA, Cheeseman, JR, Montgomery, JA, Vreven, T, Kudin, KN, and Burant, JC (2004). Gaussian 03, Revision D01, Gaussian, Inc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.3390\/ijms10093918","article-title":"A proline-based neuraminidase inhibitor: DFT studies on the zwitterion conformation, stability and formation","volume":"10","author":"Yang","year":"2009","journal-title":"Int. J. Mol. Sci"},{"key":"ref_51","unstructured":"(2005). Affinity User Guide, Accelrys Inc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1063\/1.432526","article-title":"Generalized Langevin equation approach for atom\/solid-surface scattering: General formulation for classical scattering off harmonic solids","volume":"64","author":"Adelman","year":"1976","journal-title":"J. Chem. Phys"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"11296","DOI":"10.1021\/jp002590t","article-title":"Theoretical studies on the origin of \u03b2-sheet twisting","volume":"104","author":"Shamovsky","year":"2000","journal-title":"J. Phys. Chem. B"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17079","DOI":"10.1021\/ja0552343","article-title":"A complete set of NMR chemical shifts and spin\u2212spin coupling constants for l-alanyl-l-alanine zwitterion and analysis of its conformational behavior","volume":"127","year":"2005","journal-title":"J. Am. Chem. Soc"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5470","DOI":"10.1021\/jp711484f","article-title":"An efficient method for calculating atomic charges of peptides and proteins from electronic populations","volume":"112","author":"Kang","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10957","DOI":"10.1021\/jp903635h","article-title":"QTAIM study of an \u03b1-helix hydrogen bond network","volume":"113","author":"LaPointe","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1021\/jp808741c","article-title":"Assembly and stabilization of multi-amino acid zwitterions by the Zn(II) ion: a computational exploration","volume":"113","author":"Yang","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s12539-009-0021-1","article-title":"First-principle conformational analysis of glycine residues in the \u03b1\u03b2-tubulin dimer","volume":"1","author":"Yang","year":"2009","journal-title":"Interdiscip. Sci.: Comput. Life Sci"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7104","DOI":"10.1021\/jp710394f","article-title":"Stabilization of amino acid zwitterions with varieties of anionic species: the intrinsic mechanism","volume":"112","author":"Yang","year":"2008","journal-title":"J. Phys. Chem. B"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/11\/12\/4932\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:03:58Z","timestamp":1760220238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/11\/12\/4932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,12,1]]},"references-count":60,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2010,12]]}},"alternative-id":["ijms11124932"],"URL":"https:\/\/doi.org\/10.3390\/ijms11124932","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2010,12,1]]}}}