{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:21:33Z","timestamp":1789906893308,"version":"4.0.1"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM137008"],"award-info":[{"award-number":["GM137008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM097569"],"award-info":[{"award-number":["GM097569"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM109045"],"award-info":[{"award-number":["GM109045"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation of Sri Lanka","doi-asserted-by":"publisher","award":["CHE1710671"],"award-info":[{"award-number":["CHE1710671"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug\u2010resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure\u2010based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the \u03b1 subunit of tryptophan synthase with experimental methods involving the whole\u2010cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L\u2010tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against \u03b1 subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3\u2010amino\u20103\u2010imino\u20102\u2010phenyldiazenylpropanamide (Compound 1) binds to the \u03b1 subunit. We also report a crystal structure of <jats:italic>Salmonella enterica<\/jats:italic> serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the \u03b1\u03b2 interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.<\/jats:p>","DOI":"10.1002\/pro.4236","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T13:55:55Z","timestamp":1636725355000},"page":"432-442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Discovery of antimicrobial agent targeting tryptophan synthase"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4805-3035","authenticated-orcid":false,"given":"Yuliana K.","family":"Bosken","sequence":"first","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizi","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Hilario","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rittik K.","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Hsin","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Niks","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanbin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Plant Pathology University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Plant Pathology University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard J.","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010En A.","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California at Riverside  Riverside California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"2019 Antibiotic resistance threats in the United States.Center for Disease Control and Prevention. Available from:https:\/\/www.cdc.gov\/drugresistance\/biggest-threats.html."},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.317.7159.657"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.VMBF-0016-2015"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw415"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1590\/s0036-46652014000400012"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2420"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20200194"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.2.1442-1150.2001"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)71332-X"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.0c00635"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0141-x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.045"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2018.1448303"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1970.tb00892.x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9728957"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2008.04.008"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2012.01.016"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi400795e"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1715259"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09642-y"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.31.1_supplement.765.12"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3825"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202004061"},{"key":"e_1_2_8_25_1","unstructured":"MarvinSketch.ChemAxon. Available from:https:\/\/www.chemaxon.com."},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja501602t"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2019.05.013"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000994"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-010-9376-y"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi700385f"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2015.12.006"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi901358j"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja106555c"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200700703"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi7003872"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10168"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(00)00129-0"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b08937"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)61017-8"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1006\/prep.1996.0082"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2007.00901.x"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444905039107"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444905036693"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910045749"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444900013780"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444996012255"},{"key":"e_1_2_8_48_1","unstructured":"Molecular Operating Environment (MOE).2018.01. 1010 Sherbrooke St. West Suite #910 Montreal QC Canada H3A 2R7: Chemical Computing Group ULC;2018."},{"key":"e_1_2_8_49_1","volume-title":"Amber 2018: University of California","author":"Case DA","year":"2018"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct400314y"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10128"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.445869"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.1630791"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9991(77)90098-5"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct400341p"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.4236","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pro.4236","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.4236","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T12:50:07Z","timestamp":1693140607000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.4236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":56,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1002\/pro.4236"],"URL":"https:\/\/doi.org\/10.1002\/pro.4236","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]},"assertion":[{"value":"2021-04-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}