{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:15:51Z","timestamp":1774030551384,"version":"3.50.1"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010221","name":"Higher Education Commision, Pakistan","doi-asserted-by":"publisher","award":["FDP Grant # 17-5\/FBSI-002\/HEC\/Sch-FDP\/2018"],"award-info":[{"award-number":["FDP Grant # 17-5\/FBSI-002\/HEC\/Sch-FDP\/2018"]}],"id":[{"id":"10.13039\/501100010221","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Due to the constantly evolving threat of antibiotic resistance, there is a dire need for novel antibacterial agents. Dihydropteroate synthase (DHPS) is a key bacterial enzyme which has been targeted for nearly a century as a means of selective treatment of microbial infections and exhibits two orthosteric binding sites \u2013 the\n                    <jats:italic>p<\/jats:italic>\n                    -aminobenzoic acid (\n                    <jats:italic>p<\/jats:italic>\n                    ABA) site and the pterin site. The former is the target of sulfonamides, the earliest class of synthetic antibiotics, and its mutant forms have conferred resistance to this drug class, diminishing its utility in the clinic. Conversely, the pterin site, which is highly conserved across bacterial species, is purported to be less tolerant of mutations, rendering it an attractive target for novel antibiotics. Inspired by this, we conducted a large virtual screen of more than 450,000 compounds from commercial databases, identifying compounds\n                    <jats:bold>8802<\/jats:bold>\n                    and\n                    <jats:bold>7034<\/jats:bold>\n                    as potential pterin-site inhibitors. Compound\n                    <jats:bold>8802<\/jats:bold>\n                    was quite attractive as a hit due to the ease of generating analogues, leading to the synthesis of novel compounds\n                    <jats:bold>LST-1<\/jats:bold>\n                    and\n                    <jats:bold>LST-2<\/jats:bold>\n                    . Rigid docking and molecular dynamics suggested favorable binding of these compounds to the pterin site of DHPS, and compound\n                    <jats:bold>8802<\/jats:bold>\n                    exhibited superior antibacterial activity compared to its analogues and\n                    <jats:bold>7034<\/jats:bold>\n                    . Fluorescence polarization assays did not indicate competitive inhibition of pterin-derived probe binding, and surface plasmon resonance (SPR) suggested these compounds bind very weakly to DHPS, in a nonspecific manner. The\n                    <jats:italic>in silico<\/jats:italic>\n                    assessment of the physicochemical and pharmacological properties predicted a favorable overall profile, indicating that these are suitable leads for further study to improve their activity and determine their precise mode of action.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0341835","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:25:01Z","timestamp":1774027501000},"page":"e0341835","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A virtual screening and molecular dynamics approach in search of novel antibiotic chemotypes"],"prefix":"10.1371","volume":"21","author":[{"given":"Tahira","family":"Noor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel C.","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah E.","family":"Snoke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyeun","family":"Noh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo","family":"Seabra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwangcheol Casey","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenglong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9206-2484","authenticated-orcid":true,"given":"Abdul Rauf","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"pone.0341835.ref001","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global Burden of Bacterial Antimicrobial Resistance 1990\u20132021: A Systematic Analysis with Forecasts to 2050","volume":"404","author":"M Naghavi","year":"2024","journal-title":"The Lancet"},{"issue":"4","key":"pone.0341835.ref002","first-page":"277","article-title":"The antibiotic resistance crisis: part 1: causes and threats","volume":"40","author":"CL Ventola","year":"2015","journal-title":"P T"},{"issue":"8","key":"pone.0341835.ref003","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41429-023-00629-8","article-title":"Antibiotics in the clinical pipeline as of December 2022","volume":"76","author":"MS Butler","year":"2023","journal-title":"J Antibiot (Tokyo)"},{"issue":"3","key":"pone.0341835.ref004","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1054\/drup.2000.0146","article-title":"Sulfonamide resistance: mechanisms and trends","volume":"3","author":"O Sk\u00f6ld","year":"2000","journal-title":"Drug Resist Updat"},{"issue":"6","key":"pone.0341835.ref005","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nsb0697-490","article-title":"Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase","volume":"4","author":"A Achari","year":"1997","journal-title":"Nat Struct Biol"},{"issue":"6072","key":"pone.0341835.ref006","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1126\/science.1214641","article-title":"Catalysis and sulfa drug resistance in dihydropteroate synthase","volume":"335","author":"M-K Yun","year":"2012","journal-title":"Science"},{"key":"pone.0341835.ref007","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/S0021-9258(18)93957-8","article-title":"The biosynthesis of folic acid. 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