{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T05:09:53Z","timestamp":1781932193387,"version":"3.54.5"},"reference-count":86,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministery of Economy and Knowledge (Spain)","award":["PGC2018-099277-B-C21"],"award-info":[{"award-number":["PGC2018-099277-B-C21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and four of its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol at the liquid\u2013crystal phase inside aqueous potassium chloride solution. We have elucidated the local structure of benzothiadiazine by means of microsecond molecular dynamics simulations of systems including a benzothiadiazine molecule or one of its derivatives. Such derivatives were obtained by the substitution of a single hydrogen site of benzothiadiazine by two different classes of chemical groups, one of them electron-donating groups (methyl and ethyl) and another one by electron-accepting groups (fluorine and trifluoromethyl). Our data have revealed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characteristics can vary significantly\u2014they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10\u201370 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of characteristic lengths between 1.6 and 2.1 \u00c5.<\/jats:p>","DOI":"10.3390\/membranes12030331","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:34:27Z","timestamp":1647812067000},"page":"331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["In Silico Drug Design of Benzothiadiazine Derivatives Interacting with Phospholipid Cell Membranes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2439-6241","authenticated-orcid":false,"given":"Zheyao","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus UPC, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3721-9634","authenticated-orcid":false,"given":"Jordi","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus UPC, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7595","DOI":"10.1073\/pnas.92.16.7595","article-title":"Disruption of cellular signalling pathways by daunomycin through destabilization of nonlamellar membrane structures","volume":"92","author":"Sastre","year":"1995","journal-title":"Proc. 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