{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:47:51Z","timestamp":1791924471336,"version":"4.3.4"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"40","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["TAR\/2022\/000231"],"award-info":[{"award-number":["TAR\/2022\/000231"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Helicobacter pylori remains a major cause of gastric diseases, while increasing antimicrobial resistance highlights the need for novel therapeutic targets. Here, we developed a comprehensive computational target-prioritization framework integrating Rosetta Stone domain-fusion analysis, subtractive genomics, metabolic pathway mapping, structural modeling, and molecular dynamics simulations to identify pathogen-specific drug targets in H. pylori J99. Twelve conserved domain families comprising 746 proteins were identified, and domain abundance showed a weak negative correlation with versatility (r = \u22120.327), suggesting functional specialization through domain expansion. Sequential filtering based on essentiality, nonhomology to the human proteome and gut microbiota, subcellular localization, and druggability prioritized five candidate proteins, with the ATP-binding protein AAD06727.1 emerging as the most promising target. AlphaFold2 modeling produced a high-confidence structure containing a conserved nucleotide-binding pocket. Molecular docking identified 5\u2032-fluorosulfonylbenzoyl-5\u2032-adenosine (FSBA) as the highest-affinity ligand (\u22127.3 kcal mol\u20131), outperforming ATP and verapamil. Triplicate 1 \u03bcs molecular dynamics simulations of apo and halo AAD06727.1 demonstrated stable rmsd, RMSF, radius of gyration, solvent-accessible surface area, hydrogen-bond occupancy, and principal component profiles, indicating preservation of structural integrity following ATP binding. Comparative simulations with the human ABCA12 nucleotide-binding domain showed conserved global architecture while revealing distinct ligand-recognition characteristics. Together, these findings identify AAD06727.1 as a structurally stable, pathogen-specific ATP-binding protein that represents a promising candidate for future structure-guided anti-H. pylori drug development.<\/jats:p>","DOI":"10.1021\/acsomega.6c05087","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:02:43Z","timestamp":1790737363000},"page":"61003-61019","source":"Crossref","is-referenced-by-count":0,"title":["Integrated In Silico\nAnalysis Reveals ABC Transporter\nATP-Binding Protein as a Therapeutic Target in\n                    <i>Helicobacter pylori<\/i>"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6546-8888","authenticated-orcid":true,"given":"Manish","family":"Kumar","sequence":"first","affiliation":[{"name":"Nitte (Deemed to be University) , , Deralakatte , , ,","place":["Mangalore, Karnataka, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. S.","family":"Santosh Kumar","sequence":"additional","affiliation":[{"name":"Kuvempu University , , Shankaraghatta , , ,","place":["Shivamogga, Karnataka, India, 577451"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-7419","authenticated-orcid":true,"given":"Ballamoole Krishna","family":"Kumar","sequence":"additional","affiliation":[{"name":"Nitte (Deemed to be University) , , Deralakatte , , ,","place":["Mangalore, Karnataka, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veena A.","family":"Shetty","sequence":"additional","affiliation":[{"name":"Nitte (Deemed to be University) , , Deralakatte , ,","place":["Mangalore, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavan","family":"Gollapalli","sequence":"additional","affiliation":[{"name":"Nitte (Deemed to be University) , , Deralakatte , , ,","place":["Mangalore, Karnataka, India, 575018"]},{"name":"Nitte (Deemed to be University) , , Deralakatte , , ,","place":["Mangalore, Karnataka, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"7","key":"2026101315081511800_cit1","doi-asserted-by":"publisher","first-page":"4155","DOI":"10.1128\/IAI.68.7.4155-4168.2000","article-title":"Comparative genomics\nof Helicobacter pylori: analysis of the outer membrane protein families","volume":"68","author":"Alm","year":"2000","journal-title":"Infect. Immun."},{"issue":"1","key":"2026101315081511800_cit2","doi-asserted-by":"publisher","first-page":"15453","DOI":"10.1038\/s41598-018-32476-1","article-title":"In silico proteomic and phylogenetic analysis of the outer membrane\nprotein repertoire of gastric Helicobacter species","volume":"8","author":"Bauwens","year":"2018","journal-title":"Sci. Rep."},{"issue":"2","key":"2026101315081511800_cit3","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1111\/gtc.12662","article-title":"Comparative proteomics\nof Helicobacter pylori strains reveals geographical features rather\nthan genomic variations","volume":"24","author":"Sugiyama","year":"2019","journal-title":"Genes Cells"},{"issue":"2","key":"2026101315081511800_cit4","doi-asserted-by":"publisher","first-page":"INTERACTIONS1001","DOI":"10.1186\/gb-2002-3-2-interactions1001","article-title":"Rosetta\nStone proteins: \u201cchance and necessity\u201d?","volume":"3","author":"Veitia","year":"2002","journal-title":"Genome Biol."},{"issue":"5","key":"2026101315081511800_cit5","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1007\/s00239-023-10129-w","article-title":"Domain\narchitecture based methods for comparative functional genomics toward\ntherapeutic drug target discovery","volume":"91","author":"Gollapalli","year":"2023","journal-title":"J. Mol. Evol."},{"issue":"12","key":"2026101315081511800_cit6","doi-asserted-by":"publisher","first-page":"5825","DOI":"10.1093\/molbev\/msab293","article-title":"eggNOG-mapper\nv2: Functional annotation, orthology\nassignments, and domain prediction at the metagenomic scale","volume":"38","author":"Cantalapiedra","year":"2021","journal-title":"Mol. Biol. Evol."},{"issue":"5","key":"2026101315081511800_cit7","doi-asserted-by":"publisher","first-page":"285","DOI":"10.6026\/97320630012285","article-title":"A comparison of Rosetta Stones in adapter protein families","volume":"12","author":"Kumar","year":"2016","journal-title":"Bioinformation"},{"issue":"2","key":"2026101315081511800_cit8","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4892","article-title":"PBITV3: A\nrobust and comprehensive tool for screening pathogenic proteomes for\ndrug targets and prioritizing vaccine candidates","volume":"33","author":"Chakraborty","year":"2024","journal-title":"Protein Sci."},{"issue":"3","key":"2026101315081511800_cit9","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s42485-021-00068-9","article-title":"Prioritization of potential drug\ntargets and antigenic vaccine candidates against Klebsiella aerogenes\nusing the computational subtractive proteome-driven approach","volume":"12","author":"Chakkyarath","year":"2021","journal-title":"J. Proteins Proteom."},{"key":"2026101315081511800_cit10","doi-asserted-by":"publisher","first-page":"4171","DOI":"10.1007\/s11030-025-11365-6","article-title":"Integrative genomics\nand structural bioinformatics uncovers AMR-associated drug targets\nand pqsH inhibitors in multidrug-resistant Pseudomonas aeruginosa\nJJPA01","volume":"30","author":"Narthanareeswaran","year":"2026","journal-title":"Mol. Divers."},{"issue":"2","key":"2026101315081511800_cit11","doi-asserted-by":"publisher","first-page":"24","DOI":"10.20517\/mrr.2023.78","article-title":"An exploratory in\nsilico analysis of bacteriocin gene clusters in the urobiome","volume":"3","author":"Jones","year":"2024","journal-title":"Microbiome Res. 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Inform."},{"key":"2026101315081511800_cit14","doi-asserted-by":"publisher","first-page":"2022.04.08.487609","DOI":"10.1101\/2022.04.08.487609","article-title":"DeepTMHMM predicts\nalpha and beta transmembrane proteins using deep neural networks","author":"Hallgren","year":"2022","journal-title":"bioRxiv"},{"issue":"7873","key":"2026101315081511800_cit15","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein\nstructure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"issue":"W1","key":"2026101315081511800_cit16","doi-asserted-by":"publisher","first-page":"W384","DOI":"10.1093\/nar\/gkt458","article-title":"GalaxyRefine:\nProtein structure refinement\ndriven by side-chain repacking","volume":"41","author":"Heo","year":"2013","journal-title":"Nucleic Acids\nRes."},{"issue":"4","key":"2026101315081511800_cit17","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1002\/prot.20530","article-title":"Main-chain conformational\ntendencies of amino acids","volume":"60","author":"Anderson","year":"2005","journal-title":"Proteins"},{"issue":"W1","key":"2026101315081511800_cit18","doi-asserted-by":"publisher","first-page":"W466","DOI":"10.1093\/nar\/gkaf421","article-title":"PrankWeb 4: a modular web server\nfor protein-ligand binding site prediction and downstream analysis","volume":"53","author":"Pola\u0301k","year":"2025","journal-title":"Nucleic Acids Res."},{"issue":"5","key":"2026101315081511800_cit19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/bmb.20966","article-title":"Using the PyMOL application to reinforce visual understanding\nof protein structure","volume":"44","author":"Rigsby","year":"2016","journal-title":"Biochem. 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Biol."},{"issue":"9","key":"2026101315081511800_cit27","doi-asserted-by":"publisher","first-page":"2861","DOI":"10.1093\/nar\/gkm167","article-title":"The domain\nstructure\nof Helicobacter pylori DnaB helicase: the N-terminal domain can be\ndispensable for helicase activity whereas the extreme C-terminal region\nis essential for its function","volume":"35","author":"Nitharwal","year":"2007","journal-title":"Nucleic Acids\nRes."},{"key":"2026101315081511800_cit28","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1186\/s12859-015-0773-z","article-title":"Phylogenomics and\nsequence-structure-function relationships in the GmrSD family of Type\nIV restriction enzymes","volume":"16","author":"Machnicka","year":"2015","journal-title":"BMC Bioinf."},{"issue":"4","key":"2026101315081511800_cit29","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1111\/mmi.13942","article-title":"Iron-sulfur\nprotein\nmaturation in Helicobacter pylori: identifying a Nfu-type cluster\ncarrier protein and its iron-sulfur protein targets","volume":"108","author":"Benoit","year":"2018","journal-title":"Mol. Microbiol."},{"issue":"6642","key":"2026101315081511800_cit30","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/41483","article-title":"The complete genome\nsequence of the gastric pathogen Helicobacter pylori","volume":"388","author":"Tomb","year":"1997","journal-title":"Nature"},{"issue":"2","key":"2026101315081511800_cit31","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.mib.2010.01.015","article-title":"Receiver\ndomain structure and function in response regulator proteins","volume":"13","author":"Bourret","year":"2010","journal-title":"Curr. Opin. Microbiol."},{"issue":"9","key":"2026101315081511800_cit32","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1128\/JB.187.9.3100-3109.2005","article-title":"Phosphorylation-independent\nactivity\nof atypical response regulators of Helicobacter pylori","volume":"187","author":"Scha\u0308r","year":"2005","journal-title":"J. Bacteriol."},{"issue":"S15","key":"2026101315081511800_cit33","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1186\/1471-2105-10-s15-s5","article-title":"Protein comparison\nat the domain architecture level","volume":"10","author":"Lee","year":"2009","journal-title":"BMC Bioinf."},{"issue":"2","key":"2026101315081511800_cit34","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1093\/molbev\/msm254","article-title":"Domain\ntree-based analysis of protein architecture evolution","volume":"25","author":"Forslund","year":"2008","journal-title":"Mol. Biol. Evol."},{"issue":"8","key":"2026101315081511800_cit35","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1002\/j.1460-2075.1982.tb01276.x","article-title":"Distantly related\nsequences in the alpha- and beta-subunits of ATP synthase, myosin,\nkinases and other ATP-requiring enzymes and a common nucleotide binding\nfold","volume":"1","author":"Walker","year":"1982","journal-title":"EMBO J."},{"issue":"2","key":"2026101315081511800_cit36","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1006\/jmbi.2001.4776","article-title":"Domain\ncombinations in archaeal,\neubacterial and eukaryotic proteomes","volume":"310","author":"Apic","year":"2001","journal-title":"J. Mol.\nBiol."},{"issue":"2","key":"2026101315081511800_cit37","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.sbi.2004.03.011","article-title":"Structure,\nfunction and evolution of multidomain proteins","volume":"14","author":"Vogel","year":"2004","journal-title":"Curr. Opin. Struct. Biol."},{"issue":"5","key":"2026101315081511800_cit38","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1002\/pro.2449","article-title":"Contribution of hydrogen bonds to protein\nstability","volume":"23","author":"Pace","year":"2014","journal-title":"Protein Sci."},{"issue":"1","key":"2026101315081511800_cit39","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S1097-2765(02)00576-2","article-title":"ATP binding to the motor domain from\nan ABC transporter drives formation of a nucleotide sandwich dimer","volume":"10","author":"Smith","year":"2002","journal-title":"Mol. Cell"},{"issue":"37","key":"2026101315081511800_cit40","doi-asserted-by":"publisher","first-page":"15152","DOI":"10.1073\/pnas.1108858108","article-title":"Snapshots of the maltose transporter\nduring ATP hydrolysis","volume":"108","author":"Oldham","year":"2011","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"issue":"2","key":"2026101315081511800_cit41","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1128\/MMBR.00031-07","article-title":"Structure, function,\nand evolution of bacterial ATP-binding cassette systems","volume":"72","author":"Davidson","year":"2008","journal-title":"Microbiol. Mol. Biol. Rev."},{"issue":"3","key":"2026101315081511800_cit42","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/nrm2646","article-title":"ABC transporters: the power to change","volume":"10","author":"Rees","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"6","key":"2026101315081511800_cit43","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/nsmb.3216","article-title":"Mechanistic\ndiversity in ATP-binding cassette (ABC) transporters","volume":"23","author":"Locher","year":"2016","journal-title":"Nat. Struct. Mol. 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