{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:43:28Z","timestamp":1785246208261,"version":"3.55.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007351","name":"Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires","doi-asserted-by":"publisher","award":["UBACYT 2015 20020150100023BA"],"award-info":[{"award-number":["UBACYT 2015 20020150100023BA"]}],"id":[{"id":"10.13039\/501100007351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT-2015-2276"],"award-info":[{"award-number":["PICT-2015-2276"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["664726"],"award-info":[{"award-number":["664726"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cheminform"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aromatic rings are important residues for biological interactions and appear to a large extent as part of protein\u2013drug and protein\u2013protein interactions. They are relevant for both protein stability and molecular recognition processes due to their natural occurrence in aromatic aminoacids (Trp, Phe, Tyr and His) as well as in designed drugs since they are believed to contribute to optimizing both affinity and specificity of drug-like molecules. Despite the mentioned relevance, the impact of aromatic clusters on protein\u2013protein and protein\u2013drug complexes is still poorly characterized, especially in those that go beyond a dimer. In this work, we studied protein\u2013drug and protein\u2013protein complexes and systematically analyzed the presence and structure of their aromatic clusters. Our results show that aromatic clusters are highly prevalent in both protein\u2013protein and protein\u2013drug complexes, and suggest that protein\u2013protein aromatic clusters have idealized interactions, probably because they were optimized by evolution, as compared to protein\u2013drug clusters that were manually designed. Interestingly, the configuration, solvent accessibility and secondary structure of aromatic residues in protein\u2013drug complexes shed light on the relation between these properties and compound affinity, allowing researchers to better design new molecules.<\/jats:p>","DOI":"10.1186\/s13321-020-00437-4","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T07:02:45Z","timestamp":1588921365000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Aromatic clusters in protein\u2013protein and protein\u2013drug complexes"],"prefix":"10.1186","volume":"12","author":[{"given":"Esteban","family":"Lanzarotti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas A.","family":"Defelipe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo A.","family":"Marti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2190-137X","authenticated-orcid":false,"given":"Adri\u00e1n G.","family":"Turjanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,8]]},"reference":[{"key":"437_CR1","doi-asserted-by":"publisher","first-page":"4808","DOI":"10.1002\/anie.201007560","volume":"50","author":"LM Salonen","year":"2011","unstructured":"Salonen LM, Ellermann M, Diederich F (2011) Aromatic rings in chemical and biological recognition: energetics and structures. Angew Chem Int Ed Engl 50:4808\u20134842. https:\/\/doi.org\/10.1002\/anie.201007560","journal-title":"Angew Chem Int Ed Engl"},{"key":"437_CR2","doi-asserted-by":"publisher","first-page":"6522","DOI":"10.2174\/13816128113199990440","volume":"19","author":"S Li","year":"2013","unstructured":"Li S, Xu Y, Shen Q, Liu X, Lu J, Chen Y et al (2013) Non-covalent interactions with aromatic rings: current understanding and implications for rational drug design. Curr Pharm Des 19:6522\u20136533","journal-title":"Curr Pharm Des"},{"key":"437_CR3","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.tips.2012.02.006","volume":"33","author":"CW Murray","year":"2012","unstructured":"Murray CW, Verdonk ML, Rees DC (2012) Experiences in fragment-based drug discovery. Trends Pharmacol Sci 33:224\u2013232. https:\/\/doi.org\/10.1016\/j.tips.2012.02.006","journal-title":"Trends Pharmacol Sci"},{"key":"437_CR4","doi-asserted-by":"publisher","first-page":"7206","DOI":"10.1021\/jm500515d","volume":"57","author":"TJ Ritchie","year":"2014","unstructured":"Ritchie TJ, Macdonald SJF (2014) Physicochemical descriptors of aromatic character and their use in drug discovery: miniperspective. J Med Chem 57:7206\u20137215. https:\/\/doi.org\/10.1021\/jm500515d","journal-title":"J Med Chem"},{"key":"437_CR5","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1016\/j.drudis.2009.07.014","volume":"14","author":"TJ Ritchie","year":"2009","unstructured":"Ritchie TJ, Macdonald SJF (2009) The impact of aromatic ring count on compound developability\u2013are too many aromatic rings a liability in drug design? Drug Discov Today. 14:1011\u20131020. https:\/\/doi.org\/10.1016\/j.drudis.2009.07.014","journal-title":"Drug Discov Today."},{"key":"437_CR6","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.drudis.2010.11.014","volume":"16","author":"TJ Ritchie","year":"2011","unstructured":"Ritchie TJ, Macdonald SJF, Young RJ, Pickett SD (2011) The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. Drug Discov Today. 16:164\u2013171. https:\/\/doi.org\/10.1016\/j.drudis.2010.11.014","journal-title":"Drug Discov Today."},{"key":"437_CR7","doi-asserted-by":"publisher","first-page":"11287","DOI":"10.1073\/pnas.0401942101","volume":"101","author":"D Rajamani","year":"2004","unstructured":"Rajamani D, Thiel S, Vajda S, Camacho CJ (2004) Anchor residues in protein\u2013protein interactions. Proc Natl Acad Sci USA. 101:11287\u201311292. https:\/\/doi.org\/10.1073\/pnas.0401942101","journal-title":"Proc Natl Acad Sci USA."},{"key":"437_CR8","doi-asserted-by":"publisher","first-page":"5772","DOI":"10.1073\/pnas.1030237100","volume":"100","author":"B Ma","year":"2003","unstructured":"Ma B, Elkayam T, Wolfson H, Nussinov R (2003) Protein\u2013protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci USA. 100:5772\u20135777. https:\/\/doi.org\/10.1073\/pnas.1030237100","journal-title":"Proc Natl Acad Sci USA."},{"key":"437_CR9","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/nrd.2016.29","volume":"15","author":"DE Scott","year":"2016","unstructured":"Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein\u2013protein interaction challenge. Nat Rev Drug Discov. 15:533. https:\/\/doi.org\/10.1038\/nrd.2016.29","journal-title":"Nat Rev Drug Discov."},{"key":"437_CR10","doi-asserted-by":"publisher","first-page":"65","DOI":"10.4155\/fmc.09.12","volume":"1","author":"G Zinzalla","year":"2009","unstructured":"Zinzalla G, Thurston DE (2009) Targeting protein\u2013protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem. 1:65\u201393. https:\/\/doi.org\/10.4155\/fmc.09.12","journal-title":"Future Med Chem."},{"key":"437_CR11","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/978-1-4939-2425-7_6","volume-title":"Protein-Protein Interactions: Methods and Applications","author":"DC Fry","year":"2015","unstructured":"Fry DC (2015) Targeting Protein-Protein Interactions for Drug Discovery. In: Meyerkord CL, Fu H (eds) Protein-Protein Interactions: Methods and Applications. Springer, New York, pp 93\u2013106. https:\/\/doi.org\/10.1007\/978-1-4939-2425-7_6"},{"key":"437_CR12","doi-asserted-by":"publisher","first-page":"e16","DOI":"10.1017\/erm.2012.10","volume":"14","author":"MC Smith","year":"2012","unstructured":"Smith MC, Gestwicki JE (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 14:e16. https:\/\/doi.org\/10.1017\/erm.2012.10","journal-title":"Expert Rev Mol Med"},{"key":"437_CR13","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1080\/17460441.2018.1430763","volume":"13","author":"M Rosell","year":"2018","unstructured":"Rosell M, Fern\u00e1ndez-Recio J (2018) Hot-spot analysis for drug discovery targeting protein-protein interactions. Expert Opin Drug Discov 13:327\u2013338. https:\/\/doi.org\/10.1080\/17460441.2018.1430763","journal-title":"Expert Opin Drug Discov"},{"key":"437_CR14","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.drudis.2017.10.016","volume":"23","author":"H Bruzzoni-Giovanelli","year":"2018","unstructured":"Bruzzoni-Giovanelli H, Alezra V, Wolff N, Dong C-Z, Tuffery P, Rebollo A (2018) Interfering peptides targeting protein\u2013protein interactions: the next generation of drugs? Drug Discov Today. 23:272\u2013285. https:\/\/doi.org\/10.1016\/j.drudis.2017.10.016","journal-title":"Drug Discov Today."},{"key":"437_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/jmbi.1998.1843","volume":"280","author":"AA Bogan","year":"1998","unstructured":"Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280:1\u20139. https:\/\/doi.org\/10.1006\/jmbi.1998.1843","journal-title":"J Mol Biol"},{"key":"437_CR16","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.1006\/jmbi.1998.2439","volume":"285","author":"L Lo Conte","year":"1999","unstructured":"Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein\u2013protein recognition sites. J Mol Biol 285:2177\u20132198","journal-title":"J Mol Biol"},{"key":"437_CR17","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/S0959-440X(02)00283-X","volume":"12","author":"WL DeLano","year":"2002","unstructured":"DeLano WL (2002) Unraveling hot spots in binding interfaces: progress and challenges. Curr Opin Struct Biol 12:14\u201320","journal-title":"Curr Opin Struct Biol"},{"key":"437_CR18","doi-asserted-by":"publisher","first-page":"10475","DOI":"10.1021\/jp0553479","volume":"109","author":"TP Tauer","year":"2005","unstructured":"Tauer TP, Sherrill CD (2005) Beyond the Benzene Dimer: an Investigation of the Additivity of \u03c0\u2212\u03c0 Interactions. J Phys Chem A 109:10475\u201310478. https:\/\/doi.org\/10.1021\/jp0553479","journal-title":"J Phys Chem A"},{"key":"437_CR19","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1021\/ci200062e","volume":"51","author":"E Lanzarotti","year":"2011","unstructured":"Lanzarotti E, Biekofsky RR, Estrin DA, Marti MA, Turjanski AG (2011) Aromatic\u2013aromatic interactions in proteins: beyond the dimer. J Chem Inf Model 51:1623\u20131633. https:\/\/doi.org\/10.1021\/ci200062e","journal-title":"J Chem Inf Model"},{"key":"437_CR20","doi-asserted-by":"publisher","first-page":"5061","DOI":"10.1021\/jm100112j","volume":"53","author":"C Bissantz","year":"2010","unstructured":"Bissantz C, Kuhn B, Stahl M (2010) A medicinal chemist\u2019s guide to molecular interactions. J Med Chem 53:5061\u20135084. https:\/\/doi.org\/10.1021\/jm100112j","journal-title":"J Med Chem"},{"key":"437_CR21","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1039\/C7MD00381A","volume":"8","author":"RF de Freitas","year":"2017","unstructured":"de Freitas RF, Schapira M (2017) A systematic analysis of atomic protein\u2013ligand interactions in the PDB. Medchemcomm. 8:1970\u20131981. https:\/\/doi.org\/10.1039\/C7MD00381A","journal-title":"Medchemcomm."},{"key":"437_CR22","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1093\/bioinformatics\/btl158","volume":"22","author":"W Li","year":"2006","unstructured":"Li W, Godzik A (2006) Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 22:1658\u20131659","journal-title":"Bioinformatics"},{"key":"437_CR23","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1758-2946-3-33","volume":"3","author":"NM O\u2019Boyle","year":"2011","unstructured":"O\u2019Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open Babel: an open chemical toolbox. J Cheminform. 3:33. https:\/\/doi.org\/10.1186\/1758-2946-3-33","journal-title":"J Cheminform."},{"key":"437_CR24","doi-asserted-by":"publisher","first-page":"6133","DOI":"10.1021\/ja0121639","volume":"124","author":"R Chelli","year":"2002","unstructured":"Chelli R, Gervasio FL, Procacci P, Schettino V (2002) Stacking and T-shape competition in aromatic-aromatic amino acid interactions. J Am Chem Soc 124:6133\u20136143","journal-title":"J Am Chem Soc"},{"key":"437_CR25","doi-asserted-by":"publisher","first-page":"9297","DOI":"10.1073\/pnas.91.20.9297","volume":"91","author":"L Brocchieri","year":"1994","unstructured":"Brocchieri L, Karlin S (1994) Geometry of interplanar residue contacts in protein structures. Proc Natl Acad Sci USA. 91:9297\u20139301","journal-title":"Proc Natl Acad Sci USA."},{"key":"437_CR26","doi-asserted-by":"publisher","first-page":"15458","DOI":"10.1074\/jbc.273.25.15458","volume":"273","author":"GB McGaughey","year":"1998","unstructured":"McGaughey GB, Gagn\u00e9 M, Rapp\u00e9 AK (1998) pi-Stacking interactions. Alive and well in proteins. J Biol Chem 273:15458\u201315463","journal-title":"J Biol Chem"},{"key":"437_CR27","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.1039\/b718519g","volume":"10","author":"S Marsili","year":"2008","unstructured":"Marsili S, Chelli R, Schettino V, Procacci P (2008) Thermodynamics of stacking interactions in proteins. Phys Chem Chem Phys. 10:2673. https:\/\/doi.org\/10.1039\/b718519g","journal-title":"Phys Chem Chem Phys."},{"issue":"suppl 1","key":"437_CR28","doi-asserted-by":"publisher","first-page":"D138","DOI":"10.1093\/nar\/gkh121","volume":"32","author":"A Bateman","year":"2004","unstructured":"Bateman A, Coin L, Durbin R, Finn RD, Hollich V, Griffiths-Jones S et al (2004) The Pfam protein families database. Nucleic Acids Res 32(suppl 1):D138\u2013D141","journal-title":"Nucleic Acids Res"},{"key":"437_CR29","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/bip.360221211","volume":"22","author":"W Kabsch","year":"1983","unstructured":"Kabsch W, Sander C (1983) DSSP: definition of secondary structure of proteins given a set of 3D coordinates. Biopolymers 22:2577\u20132637","journal-title":"Biopolymers"},{"key":"437_CR30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph\u00a014:33\u201338","journal-title":"J Mol Graph"},{"key":"437_CR31","doi-asserted-by":"publisher","first-page":"D198","DOI":"10.1093\/nar\/gkl999","volume":"35","author":"T Liu","year":"2007","unstructured":"Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK (2007) BindingDB: a web-accessible database of experimentally determined protein\u2013ligand binding affinities. Nucleic Acids Res 35:D198\u2013D201. https:\/\/doi.org\/10.1093\/nar\/gkl999","journal-title":"Nucleic Acids Res"},{"key":"437_CR32","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1016\/j.jmb.2013.06.030","volume":"425","author":"IL Budyak","year":"2013","unstructured":"Budyak IL, Zhuravleva A, Gierasch LM (2013) The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of \u03b2-Sheets. J Mol Biol 425:3522\u20133535. https:\/\/doi.org\/10.1016\/j.jmb.2013.06.030","journal-title":"J Mol Biol"},{"key":"437_CR33","doi-asserted-by":"publisher","first-page":"5845","DOI":"10.1021\/jm4017625","volume":"57","author":"RD Taylor","year":"2014","unstructured":"Taylor RD, MacCoss M, Lawson ADG (2014) Rings in drugs. J Med Chem 57:5845\u20135859. https:\/\/doi.org\/10.1021\/jm4017625","journal-title":"J Med Chem"}],"container-title":["Journal of Cheminformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-020-00437-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13321-020-00437-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13321-020-00437-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T23:18:23Z","timestamp":1620429503000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcheminf.biomedcentral.com\/articles\/10.1186\/s13321-020-00437-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,8]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["437"],"URL":"https:\/\/doi.org\/10.1186\/s13321-020-00437-4","relation":{},"ISSN":["1758-2946"],"issn-type":[{"value":"1758-2946","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,8]]},"assertion":[{"value":"2 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors have declared that no competing interests exist.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30"}}