{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:16:01Z","timestamp":1788419761885,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["No.3\/1\/3\/PDF\/IH &HRD-2022"],"award-info":[{"award-number":["No.3\/1\/3\/PDF\/IH &HRD-2022"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>\n                    The widespread use of antibiotics, particularly ciprofloxacin, has accelerated the emergence of antibiotic-resistant bacteria, posing a major public health challenge. Limited investment and declining pharmaceutical interest have slowed the discovery of new antibiotics, contributing to the increasing prevalence of multidrug-resistant (MDR) infections, especially those caused by ESKAPE pathogens. Uropathogenic\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (UPEC), a leading cause of urinary tract infections (UTIs), develops multidrug resistance through mechanisms including drug target modification and reduced antibiotic susceptibility. In the present study, a series of ciprofloxacin-sulfonamide hybrid molecules (CIS1-CIS15) was designed, in which each pharmacophore retains its established mechanism of action. Ciprofloxacin inhibits DNA gyrase and topoisomerase IV, whereas sulfonamides inhibit dihydropteroate synthase (DHPS) by competing with para-aminobenzoic acid (PABA) in the bacterial folate biosynthetic pathway. Accordingly, the designed hybrids were computationally evaluated against both enzymatic targets to investigate their potential dual-target antibacterial activity. Molecular docking and molecular dynamics (MD) simulations were performed to assess the binding affinity and stability of the ciprofloxacin-bearing sulfonamide derivatives (CIS1-CIS15) against DNA gyrase and\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    DHPS. Principal component analysis (PCA) and free-energy landscape (FEL) analysis were used to characterize the conformational flexibility and low-energy states of the protein\u2013ligand complexes, while MD simulations validated the stability of the highest-scoring docked complexes. Among the designed derivatives, CIS4 (ciprofloxacin-sulfamethoxazole), CIS5 (ciprofloxacin\u2013sulfaguanidine), and CIS12 (ciprofloxacin-sulfamerazine) exhibited the strongest binding affinity toward both targets while maintaining conformational stability throughout the simulations. Structural analysis of the pre- and post-MD trajectories identified Arg52, Lys39, Arg88, Lys94, Lys120, Glu201, and Lys203 as key residues involved in ligand recognition. Overall, CIS4, CIS5, and CIS12 emerged as the most promising dual-target inhibitor of bacterial DHPS and DNA gyrase. These findings provide valuable structural insights for the rational design of novel fluoroquinolone-based antibacterial agents and demonstrate the utility of computational approaches in identifying potential therapeutics against drug-resistant bacterial pathogens.\n                  <\/jats:p>","DOI":"10.3389\/fbinf.2026.1876643","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:40:18Z","timestamp":1788417618000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["All-atoms MD simulations study of newly designed ciprofloxacin derivatives as potential bacterial DHPS and DNA gyrase inhibitors"],"prefix":"10.3389","volume":"6","author":[{"given":"Chita Ranjan","family":"Sahoo","sequence":"first","affiliation":[{"name":"Department of Health Research, ICMR-Regional Medical Research Centre, Ministry of Health and Family Welfare, Government of India","place":["Bhubaneswar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhusmita","family":"Rout","sequence":"additional","affiliation":[{"name":"Department of Health Research, ICMR-Regional Medical Research Centre, Ministry of Health and Family Welfare, Government of India","place":["Bhubaneswar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudhir Kumar","family":"Paidesetty","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Laboratory, School of Pharmaceutical Sciences, Siksha \u2018O\u2019 Anusandhan Deemed to be University","place":["Bhubaneswar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Budheswar","family":"Dehury","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education","place":["Manipal, Karnataka, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debdutta","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Health Research, ICMR-Regional Medical Research Centre, Ministry of Health and Family Welfare, Government of India","place":["Bhubaneswar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghamitra","family":"Pati","sequence":"additional","affiliation":[{"name":"Department of Health Research, ICMR-Regional Medical Research Centre, Ministry of Health and Family Welfare, Government of India","place":["Bhubaneswar, India"]},{"name":"Indian Council of Medical Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.nmni.2018.08.001","article-title":"Genotypic characterization of Staphylococcus aureus isolated from a burn centre by using agr, spa and SCCmec typing methods","volume":"26","author":"Abbasian","year":"2018","journal-title":"New Microbes New Infect."},{"key":"B2","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3390\/antibiotics13050400","article-title":"Prevalence of infections and Antimicrobial Resistance of ESKAPE Group bacteria isolated from patients admitted to the intensive care unit of a county emergency Hospital in Romania","volume":"13","author":"Bereanu","year":"2024","journal-title":"Antibiotics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1086\/595011","article-title":"Bad bugs, no drugs: no ESKAPE! an update from the infectious diseases Society of America","volume":"48","author":"Boucher","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"10048","DOI":"10.1038\/ncomms10048","article-title":"Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin","volume":"6","author":"Chan","year":"2015","journal-title":"Nat. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"6929","DOI":"10.3390\/molecules28196929","article-title":"Novel fluoroquinolones with possible antibacterial activity in gram-negative resistant pathogens: In Silico drug discovery","volume":"28","author":"Coba-Males","year":"2023","journal-title":"Molecules"},{"key":"B6","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ijmm.2013.02.009","article-title":"Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions","volume":"303","author":"Cox","year":"2013","journal-title":"Int. J. Med. Microbiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1086\/323130","article-title":"Device\u2010Associated infections: a macroproblem that starts with microadherence","volume":"33","author":"Darouiche","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3492","DOI":"10.1080\/07391102.2023.2214232","article-title":"All-atoms molecular dynamics study to screen potent efflux pump inhibitors against KpnE protein of Klebsiella pneumoniae","volume":"42","author":"Dey","year":"2024","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.32607\/20758251-2018-10-4-33-48","article-title":"Bacterial enzymes and antibiotic resistance","volume":"10","author":"Egorov","year":"2018","journal-title":"Acta Naturae"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e1619","DOI":"10.1371\/journal.pone.0001619","article-title":"The neglected intrinsic resistome of bacterial pathogens","volume":"3","author":"Fajardo","year":"2008","journal-title":"PLoS ONE"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1007\/s00706-018-2215-x","article-title":"Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules","volume":"149","author":"Fedorowicz","year":"2018","journal-title":"Monatsh. F\u00fcr Chem. - Chem. Mon."},{"key":"B12","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.ejmech.2019.06.071","article-title":"Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents","volume":"179","author":"Fedorowicz","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"115373","DOI":"10.1016\/j.ejmech.2023.115373","article-title":"Antibacterial and antibiofilm activity of permanently ionized quaternary ammonium fluoroquinolones","volume":"254","author":"Fedorowicz","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/j.csbj.2022.04.025","article-title":"Contribution of hydrophobic interactions to protein mechanical stability","volume":"20","author":"Ferenczy","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4181","DOI":"10.2174\/0929867330666221128142730","article-title":"Recent advances in biological active sulfonamide based Hybrid compounds part C: multicomponent sulfonamide hybrids","volume":"30","author":"Ghomashi","year":"2023","journal-title":"Curr. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical dynamics: equilibrium phase-space distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"114021","DOI":"10.1016\/j.ejmech.2021.114021","article-title":"Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: potency and side effects","volume":"228","author":"Ibrahim","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"103499","DOI":"10.1016\/j.arabjc.2021.103499","article-title":"QSAR based virtual screening derived identification of a novel hit as a SARS CoV-229E 3CLpro Inhibitor: GA-MLR QSAR modeling supported by molecular Docking, molecular dynamics simulation and MMGBSA calculation approaches","volume":"15","author":"Jawarkar","year":"2022","journal-title":"Arabian J. Chem."},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1080\/14656566.2018.1442826","article-title":"Current and future treatment options for community-associated MRSA infection","volume":"19","author":"Khan","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"dlae127","DOI":"10.1093\/jacamr\/dlae127","article-title":"Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation","volume":"6","author":"Kherroubi","year":"2024","journal-title":"JAC-Antimicrobial Resist."},{"key":"B24","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1111\/cgf.13072","article-title":"Visualization of biomolecular structures: state of the art revisited","volume":"36","author":"Kozl\u00edkov\u00e1","year":"2017","journal-title":"Comput. Graph. Forum"},{"key":"B25","doi-asserted-by":"publisher","first-page":"13497","DOI":"10.1080\/07391102.2021.1989040","article-title":"Exploring the interaction mechanism between potential inhibitor and multi-target Mur enzymes of mycobacterium tuberculosis using molecular docking, molecular dynamics simulation, principal component analysis, free energy landscape, dynamic cross-correlation matrices, vector movements, and binding free energy calculation","volume":"40","author":"Kumari","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B26","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41579-021-00649-x","article-title":"Antibiotic resistance in the environment","volume":"20","author":"Larsson","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"Lowy","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"B29","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Madhavi Sastry","year":"2013","journal-title":"J. Computer-Aided Mol. Des."},{"key":"B30","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/82_2016_3","volume-title":"Worldwide Epidemiology and Antibiotic Resistance of Staphylococcus aureus","author":"Monaco","year":"2016"},{"key":"B31","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1080\/00268978400101201","article-title":"A molecular dynamics method for simulations in the canonical ensemble","volume":"52","author":"Nos\u00e9","year":"1984","journal-title":"Mol. Phys."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3526","DOI":"10.1080\/07391102.2023.2298735","article-title":"Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of Aspergillus fumigatus: a potential target for antimycotics","volume":"43","author":"Panda","year":"2025","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B33","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s00726-007-0015-4","article-title":"Strong and weak hydrogen bonds in protein-ligand complexes of kinases: a comparative study","volume":"34","author":"Panigrahi","year":"2008","journal-title":"Amino Acids"},{"key":"B34","doi-asserted-by":"publisher","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: a new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"B35","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jgar.2016.07.010","article-title":"Methicillin-resistant Staphylococcus aureus infections: a review of the currently available treatment options","volume":"7","author":"Purrello","year":"2016","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"B36","doi-asserted-by":"publisher","first-page":"8778","DOI":"10.1021\/acs.jmedchem.9b01129","article-title":"Practical high-quality electrostatic potential surfaces for drug discovery using a graph-convolutional deep neural network","volume":"63","author":"Rathi","year":"2019","journal-title":"J. Med. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"107116","DOI":"10.1016\/j.compbiomed.2023.107116","article-title":"Exploiting the potential of natural polyphenols as antivirals against monkeypox envelope protein F13 using machine learning and all-atoms MD simulations","volume":"162","author":"Rout","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3935","DOI":"10.1080\/07391102.2023.2216290","article-title":"Machine learning and classical MD simulation to identify inhibitors against the P37 envelope protein of monkeypox virus","volume":"42","author":"Rout","year":"2024","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B39","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1211\/jpp.59.5.0013","article-title":"Antiproliferative, cytotoxic and antitumour activity of coumarins isolated from Calophyllum brasiliense","volume":"59","author":"Ruiz-Marcial","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5419","DOI":"10.1080\/07391102.2019.1701554","article-title":"Molecular dynamics and computational study of Mannich-based coumarin derivatives: potent tyrosine kinase inhibitor","volume":"38","author":"Sahoo","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B41","doi-asserted-by":"publisher","first-page":"9487","DOI":"10.1080\/07391102.2025.2459263","article-title":"Molecular simulation of newly designed Mannich-based ciprofloxacin derivative as the promising scaffold for E. coli dihydropteroate synthase and DNA gyrase inhibitor","volume":"43","author":"Sahoo","year":"2025","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B42","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: a software program for pK a prediction and protonation state generation for drug-like molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J. Computer-Aided Mol. Des."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.1128\/microbiolspec.GPP3-0039-2018","article-title":"Staphylococcus aureus secreted toxins and extracellular enzymes","volume":"7","author":"Tam","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM general force Field (CGenFF) I: bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1016\/j.csbj.2020.06.029","article-title":"Protein electrostatics: from computational and structural analysis to discovery of functional fingerprints and biotechnological design","volume":"18","author":"Vascon","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B46","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1107\/S2059798316001212","article-title":"Structure of a quinolone-stabilized cleavage complex of topoisomerase IV from Klebsiella pneumoniae and comparison with a related Streptococcus pneumoniae complex","volume":"72","author":"Veselkov","year":"2016","journal-title":"Acta Crystallogr. Sect. D. Struct. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/35021219","article-title":"Molecular mechanisms that confer antibacterial drug resistance","volume":"406","author":"Walsh","year":"2000","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"bbac384","DOI":"10.1093\/bib\/bbac384","article-title":"A geometric deep learning framework for drug repositioning over heterogeneous information networks","volume":"23","author":"Zhao","year":"2022","journal-title":"Briefings Bioinforma."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1038\/s42256-025-01077-9","article-title":"Protein\u2013peptide docking with a rational and accurate diffusion generative model","volume":"7","author":"Zhao","year":"2025","journal-title":"Nat. Mach. Intell."},{"key":"B50","doi-asserted-by":"publisher","first-page":"5008","DOI":"10.1021\/acs.jcim.6c00311","article-title":"DRHIN: an integrated and interactive web server for drug repositioning","volume":"66","author":"Zhao","year":"2026","journal-title":"J. Chem. Inf. Model."}],"container-title":["Frontiers in Bioinformatics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2026.1876643\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:40:20Z","timestamp":1788417620000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2026.1876643\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":50,"alternative-id":["10.3389\/fbinf.2026.1876643"],"URL":"https:\/\/doi.org\/10.3389\/fbinf.2026.1876643","relation":{},"ISSN":["2673-7647"],"issn-type":[{"value":"2673-7647","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"1876643"}}