Targeting SARS-CoV-2 variants with Bromelain: an in-silico study of Spike-ACE2 inhibition using docking, molecular dynamic simulation, and MM-PBSA

Ahuja et al., In Silico Pharmacology, doi:10.1007/s40203-025-00446-x, Oct 2025
In silico study showing bromelain may inhibit SARS-CoV-2 by acting as a competitive inhibitor of Spike-ACE2 interaction. Authors utilized docking, molecular dynamics simulation, and MM/PBSA to test bromelain against the spike protein receptor-binding domain (RBD) of the Wuhan, Delta, Omicron, JN.1.1, and JN.1.4 variants.
Ahuja et al., 17 Oct 2025, peer-reviewed, 3 authors.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
DOI record: { "DOI": "10.1007/s40203-025-00446-x", "ISSN": [ "2193-9616" ], "URL": "http://dx.doi.org/10.1007/s40203-025-00446-x", "alternative-id": [ "446" ], "article-number": "157", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "29 August 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "29 September 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "17 October 2025" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "The authors declare no competing interests." }, { "group": { "label": "Ethical approval", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "Not applicable." }, { "group": { "label": "Consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 4, "value": "All authors consent for the publication." } ], "author": [ { "ORCID": "https://orcid.org/0009-0004-9324-9506", "affiliation": [], "authenticated-orcid": false, "family": "Ahuja", "given": "Palash", "sequence": "first" }, { "ORCID": "https://orcid.org/0009-0006-1448-2698", "affiliation": [], "authenticated-orcid": false, "family": "Rao", "given": "Lawanya", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-9487-6246", "affiliation": [], "authenticated-orcid": false, "family": "Dsouza", "given": "Norine", "sequence": "additional" } ], "container-title": "In Silico Pharmacology", "container-title-short": "In Silico Pharmacol.", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2025, 10, 17 ] ], "date-time": "2025-10-17T16:29:03Z", "timestamp": 1760718543000 }, "deposited": { "date-parts": [ [ 2025, 10, 17 ] ], "date-time": "2025-10-17T16:29:05Z", "timestamp": 1760718545000 }, "indexed": { "date-parts": [ [ 2025, 10, 17 ] ], "date-time": "2025-10-17T17:12:27Z", "timestamp": 1760721147627, "version": "build-2065373602" }, "is-referenced-by-count": 0, "issue": "3", "issued": { "date-parts": [ [ 2025, 10, 17 ] ] }, "journal-issue": { "issue": "3", "published-online": { "date-parts": [ [ 2025, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://www.springernature.com/gp/researchers/text-and-data-mining", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 10, 17 ] ], "date-time": "2025-10-17T00:00:00Z", "timestamp": 1760659200000 } }, { "URL": "https://www.springernature.com/gp/researchers/text-and-data-mining", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 10, 17 ] ], "date-time": "2025-10-17T00:00:00Z", "timestamp": 1760659200000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1007/s40203-025-00446-x.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1007/s40203-025-00446-x/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1007/s40203-025-00446-x.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1007", "published": { "date-parts": [ [ 2025, 10, 17 ] ] }, "published-online": { "date-parts": [ [ 2025, 10, 17 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1016/j.sjbs.2020.11.032", "author": "S Abbas", "doi-asserted-by": "publisher", "first-page": "1001", "issue": "1", "journal-title": "Saudi J Biol Sci", "key": "446_CR1", "unstructured": "Abbas S, Shanbhag T, Kothare A (2021) Applications of bromelain from pineapple waste towards acne. Saudi J Biol Sci 28(1):1001–1009. https://doi.org/10.1016/j.sjbs.2020.11.032", "volume": "28", "year": "2021" }, { "DOI": "10.1016/j.softx.2015.06.001", "author": "MJ Abraham", "doi-asserted-by": "publisher", "first-page": "19", "journal-title": "SoftwareX", "key": "446_CR2", "unstructured": "Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1:19–25. https://doi.org/10.1016/j.softx.2015.06.001", "volume": "1", "year": "2015" }, { "DOI": "10.1038/srep34984", "author": "I Aier", "doi-asserted-by": "publisher", "first-page": "34984", "issue": "1", "journal-title": "Sci Rep", "key": "446_CR3", "unstructured": "Aier I, Varadwaj PK, Raj U (2016) Structural insights into conformational stability of both wild-type and mutant EZH2 receptor. Sci Rep 6(1):34984. https://doi.org/10.1038/srep34984", "volume": "6", "year": "2016" }, { "DOI": "10.1101/2020.09.07.286906", "author": "J Akhter", "doi-asserted-by": "publisher", "journal-title": "Viruses", "key": "446_CR4", "unstructured": "Akhter J, Queromes G, Pillai K, Kepenekian V, Badar S, Mekkawy A, Morris DL (2020) In vitro study of BromAc on SARS-CoV-2 spike and envelope proteins shows synergy and disintegration at modest concentrations. Viruses. https://doi.org/10.1101/2020.09.07.286906", "year": "2020" }, { "DOI": "10.1186/s40001-022-00818-5", "author": "HM Al-Kuraishy", "doi-asserted-by": "publisher", "first-page": "186", "issue": "1", "journal-title": "Eur J Med Res", "key": "446_CR5", "unstructured": "Al-Kuraishy HM, Al-Fakhrany OM, Elekhnawy E, Al-Gareeb AI, Alorabi M, De Waard M, Batiha GES (2022) Traditional herbs against COVID-19: back to old weapons to combat the new pandemic. Eur J Med Res 27(1):186. https://doi.org/10.1186/s40001-022-00818-5", "volume": "27", "year": "2022" }, { "DOI": "10.1002/jmv.27588", "author": "Y Araf", "doi-asserted-by": "publisher", "first-page": "1825", "issue": "5", "journal-title": "J Med Virol", "key": "446_CR6", "unstructured": "Araf Y, Akter F, Tang YD, Fatemi R, Parvez MSA, Zheng C, Hossain MG (2022) Omicron variant of SARS-CoV-2: genomics, transmissibility, and responses to current COVID-19 vaccines. J Med Virol 94(5):1825–1832. https://doi.org/10.1002/jmv.27588", "volume": "94", "year": "2022" }, { "DOI": "10.17179/excli2023-6098", "author": "P Bhardwaj", "doi-asserted-by": "publisher", "first-page": "451", "journal-title": "EXCLI J", "key": "446_CR7", "unstructured": "Bhardwaj P, Mishra SK, Behera SP, Zaman K, Kant R, Singh R (2023) Genomic evolution of the SARS-CoV-2 variants of concern: COVID-19 pandemic waves in India. EXCLI J 22:451. https://doi.org/10.17179/excli2023-6098", "volume": "22", "year": "2023" }, { "DOI": "10.1007/s11033-022-08193-4", "author": "S Borkotoky", "doi-asserted-by": "publisher", "first-page": "2713", "issue": "3", "journal-title": "Mol Biol Rep", "key": "446_CR8", "unstructured": "Borkotoky S, Dey D, Hazarika Z (2023) Interactions of angiotensin-converting enzyme-2 (ACE2) and SARS-CoV-2 spike receptor-binding domain (RBD): a structural perspective. Mol Biol Rep 50(3):2713–2721. https://doi.org/10.1007/s11033-022-08193-4", "volume": "50", "year": "2023" }, { "DOI": "10.1152/ajpgi.1997.273.1.G139", "author": "JV Castell", "doi-asserted-by": "publisher", "first-page": "G139", "issue": "1", "journal-title": "Am J Physiol Gastrointest Liver Physiol", "key": "446_CR9", "unstructured": "Castell JV, Friedrich G, Kuhn CS, Poppe GE (1997) Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol Gastrointest Liver Physiol 273(1):G139–G146. https://doi.org/10.1152/ajpgi.1997.273.1.G139", "volume": "273", "year": "1997" }, { "DOI": "10.1007/s00284-022-03094-y", "author": "S Chakraborti", "doi-asserted-by": "publisher", "first-page": "1", "issue": "1", "journal-title": "Curr Microbiol", "key": "446_CR10", "unstructured": "Chakraborti S, Gill J, Goswami R, Kumar S, Chandele A, Sharma A (2023) Structural profiles of SARS-CoV-2 variants in India. Curr Microbiol 80(1):1. https://doi.org/10.1007/s00284-022-03094-y", "volume": "80", "year": "2023" }, { "DOI": "10.3390/life11040317", "author": "AJ Chakraborty", "doi-asserted-by": "publisher", "first-page": "317", "issue": "4", "journal-title": "Life", "key": "446_CR11", "unstructured": "Chakraborty AJ, Mitra S, Tallei TE, Tareq AM, Nainu F, Cicia D, Capasso R (2021) Bromelain a potential bioactive compound: a comprehensive overview from a pharmacological perspective. Life 11(4):317. https://doi.org/10.3390/life11040317", "volume": "11", "year": "2021" }, { "DOI": "10.3390/v15010167", "author": "S Chatterjee", "doi-asserted-by": "publisher", "first-page": "167", "issue": "1", "journal-title": "Viruses", "key": "446_CR12", "unstructured": "Chatterjee S, Bhattacharya M, Nag S, Dhama K, Chakraborty C (2023) A detailed overview of SARS-CoV-2 omicron: its sub-variants, mutations and pathophysiology, clinical characteristics, immunological landscape, immune escape, and therapies. Viruses 15(1):167. https://doi.org/10.3390/v15010167", "volume": "15", "year": "2023" }, { "DOI": "10.3390/vaccines11010160", "author": "VP Chavda", "doi-asserted-by": "publisher", "first-page": "160", "issue": "1", "journal-title": "Vaccines", "key": "446_CR13", "unstructured": "Chavda VP, Balar P, Vaghela D, Solanki HK, Vaishnav A, Hala V, Vora L (2023) Omicron variant of SARS-CoV-2: an Indian perspective of vaccination and management. Vaccines 11(1):160. https://doi.org/10.3390/vaccines11010160", "volume": "11", "year": "2023" }, { "DOI": "10.1002/pro.2230", "author": "J Chen", "doi-asserted-by": "publisher", "first-page": "510", "issue": "4", "journal-title": "Protein Sci", "key": "446_CR14", "unstructured": "Chen J, Sawyer N, Regan L (2013) Protein–protein interactions: general trends in the relationship between binding affinity and interfacial buried surface area. Protein Sci 22(4):510–515. https://doi.org/10.1002/pro.2230", "volume": "22", "year": "2013" }, { "DOI": "10.1016/j.canlet.2009.08.001", "author": "K Chobotova", "doi-asserted-by": "publisher", "first-page": "148", "issue": "2", "journal-title": "Cancer Lett", "key": "446_CR15", "unstructured": "Chobotova K, Vernallis AB, Majid FAA (2010) Bromelain’s activity and potential as an anti-cancer agent: current evidence and perspectives. Cancer Lett 290(2):148–156. https://doi.org/10.1016/j.canlet.2009.08.001", "volume": "290", "year": "2010" }, { "DOI": "10.1016/j.cellin.2023.100144", "author": "M Dong", "doi-asserted-by": "publisher", "first-page": "100144", "issue": "1", "journal-title": "Cell Insight", "key": "446_CR16", "unstructured": "Dong M, Achi JMG, Du R, Rong L, Cui Q (2024) Development of SARS-CoV-2 entry antivirals. Cell Insight 3(1):100144. https://doi.org/10.1016/j.cellin.2023.100144", "volume": "3", "year": "2024" }, { "DOI": "10.7759/cureus.41295", "author": "P Gupta", "doi-asserted-by": "publisher", "first-page": "41295", "issue": "7", "journal-title": "Cureus", "key": "446_CR17", "unstructured": "Gupta P, Gupta V, Singh CM, Singhal L (2023) Emergence of COVID-19 variants: an update. Cureus 15(7):41295. https://doi.org/10.7759/cureus.41295", "volume": "15", "year": "2023" }, { "DOI": "10.1016/j.cell.2022.01.001", "author": "P Han", "doi-asserted-by": "publisher", "first-page": "630", "issue": "4", "journal-title": "Cell", "key": "446_CR18", "unstructured": "Han P, Li L, Liu S, Wang Q, Zhang D, Xu Z, Wang P (2022) Receptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2. Cell 185(4):630–640. https://doi.org/10.1016/j.cell.2022.01.001", "volume": "185", "year": "2022" }, { "DOI": "10.3390/nu13124313", "author": "P Hikisz", "doi-asserted-by": "publisher", "first-page": "4313", "issue": "12", "journal-title": "Nutrients", "key": "446_CR19", "unstructured": "Hikisz P, Bernasinska-Slomczewska J (2021) Beneficial properties of bromelain. Nutrients 13(12):4313. https://doi.org/10.3390/nu13124313", "volume": "13", "year": "2021" }, { "DOI": "10.1038/s41596-024-01011-0", "author": "RV Honorato", "doi-asserted-by": "publisher", "first-page": "3219", "issue": "11", "journal-title": "Nat Protoc", "key": "446_CR20", "unstructured": "Honorato RV, Trellet ME, Jiménez-García B, Schaarschmidt JJ, Giulini M, Reys V, Bonvin AM (2024) The HADDOCK2. 4 web server for integrative modeling of biomolecular complexes. Nat Protoc 19(11):3219–3241. https://doi.org/10.1038/s41596-024-01011-0", "volume": "19", "year": "2024" }, { "DOI": "10.1038/s41401-020-0485-4", "author": "Y Huang", "doi-asserted-by": "publisher", "first-page": "1141", "issue": "9", "journal-title": "Acta Pharmacol Sin", "key": "446_CR21", "unstructured": "Huang Y, Yang C, Xu XF, Xu W, Liu SW (2020) Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin 41(9):1141–1149. https://doi.org/10.1038/s41401-020-0485-4", "volume": "41", "year": "2020" }, { "DOI": "10.1515/hmbci-2023-0088", "author": "P Kamble", "doi-asserted-by": "publisher", "first-page": "49", "issue": "2", "journal-title": "Horm Mol Biol Clin Investig", "key": "446_CR22", "unstructured": "Kamble P, Daulatabad V, Singhal A, Ahmed ZS, Choubey A, Bhargava S, John NA (2024) JN. 1 variant in enduring COVID-19 pandemic: is it a variety of interest (VoI) or variety of concern (VoC)? Horm Mol Biol Clin Investig 45(2):49–53. https://doi.org/10.1515/hmbci-2023-0088", "volume": "45", "year": "2024" }, { "DOI": "10.7759/cureus.56718", "author": "RP Karyakarte", "doi-asserted-by": "publisher", "first-page": "56718", "issue": "3", "journal-title": "Cureus", "key": "446_CR23", "unstructured": "Karyakarte RP, Das R, Rajmane MV, Dudhate S, Agarasen J, Pillai P, Kulkarni P Jr (2024) Appearance and prevalence of JN. 1 SARS-CoV-2 variant in India and its clinical profile in the state of Maharashtra. Cureus 16(3):56718. https://doi.org/10.7759/cureus.56718", "volume": "16", "year": "2024" }, { "DOI": "10.1016/j.metop.2020.100066", "author": "P Kritis", "doi-asserted-by": "publisher", "first-page": "100066", "journal-title": "Metab Open", "key": "446_CR24", "unstructured": "Kritis P, Karampela I, Kokoris S, Dalamaga M (2020) The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19. Metab Open 8:100066. https://doi.org/10.1016/j.metop.2020.100066", "volume": "8", "year": "2020" }, { "DOI": "10.1016/0014-2999(88)90010", "author": "S Kumakura", "doi-asserted-by": "publisher", "first-page": "295", "issue": "3", "journal-title": "Eur J Pharmacol", "key": "446_CR25", "unstructured": "Kumakura S, Yamashita M, Tsurufuji S (1988) Effect of bromelain on kaolin-induced inflammation in rats. Eur J Pharmacol 150(3):295–301. https://doi.org/10.1016/0014-2999(88)90010", "volume": "150", "year": "1988" }, { "DOI": "10.1002/pro.3289", "author": "RA Laskowski", "doi-asserted-by": "publisher", "first-page": "129", "issue": "1", "journal-title": "Protein Sci", "key": "446_CR26", "unstructured": "Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM (2018) PDBsum: structural summaries of PDB entries. Protein Sci 27(1):129–134. https://doi.org/10.1002/pro.3289", "volume": "27", "year": "2018" }, { "DOI": "10.1002/mco2.675", "author": "Y Lu", "doi-asserted-by": "publisher", "first-page": "e675", "issue": "8", "journal-title": "MedComm", "key": "446_CR27", "unstructured": "Lu Y, Ao D, He X, Wei X (2024) The rising SARS-CoV-2 JN. 1 variant: evolution, infectivity, immune escape, and response strategies. MedComm 5(8):e675. https://doi.org/10.1002/mco2.675", "volume": "5", "year": "2024" }, { "DOI": "10.1016/0098-3004(93)90090-r", "author": "A Maćkiewicz", "doi-asserted-by": "publisher", "first-page": "303", "issue": "3", "journal-title": "Comput Geosci", "key": "446_CR28", "unstructured": "Maćkiewicz A, Ratajczak W (1993) Principal components analysis (PCA). Comput Geosci 19(3):303–342. https://doi.org/10.1016/0098-3004(93)90090-r", "volume": "19", "year": "1993" }, { "DOI": "10.1002/pro.4792", "author": "EC Meng", "doi-asserted-by": "publisher", "first-page": "e4792", "issue": "11", "journal-title": "Protein Sci", "key": "446_CR29", "unstructured": "Meng EC, Goddard TD, Pettersen EF, Couch GS, Pearson ZJ, Morris JH, Ferrin TE (2023) UCSF ChimeraX: tools for structure building and analysis. Protein Sci 32(11):e4792. https://doi.org/10.1002/pro.4792", "volume": "32", "year": "2023" }, { "DOI": "10.1021/ct300418h", "author": "BR Miller III", "doi-asserted-by": "publisher", "first-page": "3314", "issue": "9", "journal-title": "J Chem Theory Comput", "key": "446_CR30", "unstructured": "Miller BR III, McGee TD Jr, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) MMPBSA. py: an efficient program for end-state free energy calculations. J Chem Theory Comput 8(9):3314–3321. https://doi.org/10.1021/ct300418h", "volume": "8", "year": "2012" }, { "DOI": "10.1007/s00894-023-05489-5", "author": "D Mitra", "doi-asserted-by": "publisher", "first-page": "91", "issue": "4", "journal-title": "J Mol Model", "key": "446_CR32", "unstructured": "Mitra D, Afreen S, Das Mohapatra PK, Abdalla M (2023a) Threat of respiratory syncytial virus infection knocking the door: a proposed potential drug candidate through molecular dynamics simulations, a future alternative. J Mol Model 29(4):91", "volume": "29", "year": "2023" }, { "DOI": "10.1080/07391102.2023.2300408", "author": "D Mitra", "doi-asserted-by": "publisher", "first-page": "2440", "issue": "5", "journal-title": "J Biomol Struct Dyn", "key": "446_CR34", "unstructured": "Mitra D, Afreen S, Das Mohapatra PK, Abdalla M (2025) Inhibition of respiratory syncytial virus by Daclatasvir and its derivatives: synthesis of computational derivatives as a new drug development. J Biomol Struct Dyn 43(5):2440–2462", "volume": "43", "year": "2025" }, { "DOI": "10.1007/s40203-023-00178-w", "author": "D Mitra", "doi-asserted-by": "publisher", "first-page": "5", "issue": "1", "journal-title": "In Silico Pharmacol", "key": "446_CR33", "unstructured": "Mitra D, Paul M, Thatoi H, Das Mohapatra PK (2023b) Potentiality of bioactive compounds as inhibitor of M protein and F protein function of human respiratory syncytial virus. In Silico Pharmacol 12(1):5", "volume": "12", "year": "2023" }, { "DOI": "10.1080/07391102.2021.1942210", "author": "D Mitra", "doi-asserted-by": "publisher", "first-page": "10239", "issue": "20", "journal-title": "J Biomol Struct Dyn", "key": "446_CR31", "unstructured": "Mitra D, Paul M, Thatoi H, Mohapatra PKD (2022) Study of potentiality of dexamethasone and its derivatives against Covid-19. J Biomol Struct Dyn 40(20):10239–10249", "volume": "40", "year": "2022" }, { "DOI": "10.1016/j.imbio.2022.152222", "author": "AG Mukherjee", "doi-asserted-by": "publisher", "first-page": "152222", "issue": "3", "journal-title": "Immunobiology", "key": "446_CR35", "unstructured": "Mukherjee AG, Wanjari UR, Murali R, Chaudhary U, Renu K, Madhyastha H, Gopalakrishnan AV (2022) Omicron variant infection and the associated immunological scenario. Immunobiology 227(3):152222. https://doi.org/10.1016/j.imbio.2022.152222", "volume": "227", "year": "2022" }, { "DOI": "10.1016/j.matpr.2021.07.163", "author": "SN Nagesha", "doi-asserted-by": "publisher", "first-page": "904", "journal-title": "Mater Today Proc", "key": "446_CR36", "unstructured": "Nagesha SN, Ramesh BN, Pradeep C, Shashidhara KS, Krishnaprasad BT, Jnanashree SM, Shreeram SC (2022) SARS-CoV 2 spike protein S1 subunit as an ideal target for stable vaccines: a bioinformatic study. Mater Today Proc 49:904–912. https://doi.org/10.1016/j.matpr.2021.07.163", "volume": "49", "year": "2022" }, { "DOI": "10.1166/asem.2014.1453", "author": "M Pandjaitan", "doi-asserted-by": "publisher", "first-page": "119", "issue": "1", "journal-title": "Adv Sci Eng Med", "key": "446_CR37", "unstructured": "Pandjaitan M, Nugraha T, Pamudja KH (2014) Bromelain enzyme in fresh pineapple juice as a healing pathway for HIV/AIDS. Adv Sci Eng Med 6(1):119–123. https://doi.org/10.1166/asem.2014.1453", "volume": "6", "year": "2014" }, { "DOI": "10.1016/j.jmgm.2009.01.006", "author": "E Papaleo", "doi-asserted-by": "publisher", "first-page": "889", "issue": "8", "journal-title": "J Mol Graph Model", "key": "446_CR38", "unstructured": "Papaleo E, Mereghetti P, Fantucci P, Grandori R, De Gioia L (2009) Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: the myoglobin case. J Mol Graph Model 27(8):889–899. https://doi.org/10.1016/j.jmgm.2009.01.006", "volume": "27", "year": "2009" }, { "DOI": "10.1155/2012/976203", "author": "R Pavan", "doi-asserted-by": "publisher", "first-page": "976203", "issue": "1", "journal-title": "Biotechnol Res Int", "key": "446_CR39", "unstructured": "Pavan R, Jain S, Shraddha, Kumar A (2012) Properties and therapeutic application of bromelain: a review. Biotechnol Res Int 2012(1):976203. https://doi.org/10.1155/2012/976203", "volume": "2012", "year": "2012" }, { "DOI": "10.3389/fonc.2022.1068778", "author": "R Pezzani", "doi-asserted-by": "publisher", "first-page": "1068778", "journal-title": "Front Oncol", "key": "446_CR40", "unstructured": "Pezzani R, Jiménez-Garcia M, Capó X, Sönmez Gürer E, Sharopov F, Rachel TYL, Ntieche Woutouoba D, Rescigno A, Peddio S, Zucca P, Tsouh Fokou PV, Martorell M, Gulsunoglu-Konuskan Z, Ydyrys A, Bekzat T, Gulmira T, Hano C, Sharifi-Rad J, Calina D (2023) Anticancer properties of bromelain: state-of-the-art and recent trends. Front Oncol 12:1068778. https://doi.org/10.3389/fonc.2022.1068778", "volume": "12", "year": "2023" }, { "DOI": "10.3892/br.2016.720", "author": "V Rathnavelu", "doi-asserted-by": "publisher", "first-page": "283", "issue": "3", "journal-title": "Biomed Rep", "key": "446_CR41", "unstructured": "Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R (2016) Potential role of bromelain in clinical and therapeutic applications. Biomed Rep 5(3):283–288. https://doi.org/10.3892/br.2016.720", "volume": "5", "year": "2016" }, { "DOI": "10.1038/s41598-025-92242-y", "author": "EVDS Reis", "doi-asserted-by": "publisher", "first-page": "1", "issue": "1", "journal-title": "Sci Rep", "key": "446_CR42", "unstructured": "Reis EVDS, Ferreira LL, Clarindo FA, Marques-Ferreira G, de Oliveira LC, Moraes TDFS, Coelho-dos-Reis JGA (2025) Antiviral effect of Bromelain combined with acetylcysteine against SARS-CoV-2 Omicron variant. Sci Rep 15(1):1–12. https://doi.org/10.1038/s41598-025-92242-y", "volume": "15", "year": "2025" }, { "DOI": "10.1186/s42269-024-01233-y", "doi-asserted-by": "publisher", "key": "446_CR61", "unstructured": "Roney M, Mohd Aluwi MFF (2024) Evolution of SARS-CoV-2 from BA. 2.86 to JN. 1 variations and detection in Bangladesh. Bull Nat Res Centre 48(1):78. https://doi.org/10.1186/s42269-024-01233-y" }, { "DOI": "10.1101/2020.09.16.297366", "author": "S Sagar", "doi-asserted-by": "publisher", "journal-title": "Biorxiv", "key": "446_CR43", "unstructured": "Sagar S, Rathinavel AK, Lutz WE, Struble LR, Khurana S, Schnaubelt AT, Radhakrishnan P (2020) Bromelain inhibits SARS-CoV-2 infection in VeroE6 cells. Biorxiv. https://doi.org/10.1101/2020.09.16.297366", "year": "2020" }, { "DOI": "10.1002/ctm2.281", "author": "S Sagar", "doi-asserted-by": "publisher", "first-page": "e281", "issue": "2", "journal-title": "Clin Transl Med", "key": "446_CR44", "unstructured": "Sagar S, Rathinavel AK, Lutz WE, Struble LR, Khurana S, Schnaubelt AT, Radhakrishnan P (2021) Bromelain inhibits SARS-CoV-2 infection via targeting ACE-2, TMPRSS2, and spike protein. Clin Transl Med 11(2):e281. https://doi.org/10.1002/ctm2.281", "volume": "11", "year": "2021" }, { "DOI": "10.1101/2024.04.16.24305882", "author": "ST Selvavinayagam", "doi-asserted-by": "publisher", "first-page": "17476", "issue": "1", "journal-title": "Sci Rep", "key": "446_CR45", "unstructured": "Selvavinayagam ST, Sankar S, Yong YK, Murugesan A, Suvaithenamudhan S, Hemashree K, Raju S (2024) Emergence of SARS-CoV-2 omicron variant JN. 1 in Tamil Nadu, India-clinical characteristics and novel mutations. Sci Rep 14(1):17476. https://doi.org/10.1101/2024.04.16.24305882", "volume": "14", "year": "2024" }, { "DOI": "10.1186/s13104-024-06995-2", "author": "AS Shamsuri", "doi-asserted-by": "publisher", "first-page": "346", "issue": "1", "journal-title": "BMC Res Notes", "key": "446_CR46", "unstructured": "Shamsuri AS, Sim EU (2024) In silico prediction of the action of bromelain on PI3K/Akt signalling pathway to arrest nasopharyngeal cancer oncogenesis by targeting phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha protein. BMC Res Notes 17(1):346. https://doi.org/10.1186/s13104-024-06995-2", "volume": "17", "year": "2024" }, { "DOI": "10.1371/journal.pone.0277849", "author": "M Sharma", "doi-asserted-by": "publisher", "first-page": "e0277849", "issue": "11", "journal-title": "PLoS ONE", "key": "446_CR47", "unstructured": "Sharma M, Gupta N, Pandey E (2022) Implications of nasal delivery of bromelain on its pharmacokinetics, tissue distribution and pharmacodynamic profile—a preclinical study. PLoS ONE 17(11):e0277849. https://doi.org/10.1371/journal.pone.0277849", "volume": "17", "year": "2022" }, { "DOI": "10.1002/pro.3290", "author": "F Sievers", "doi-asserted-by": "publisher", "first-page": "135", "issue": "1", "journal-title": "Protein Sci", "key": "446_CR48", "unstructured": "Sievers F, Higgins DG (2018) Clustal omega for making accurate alignments of many protein sequences. Protein Sci 27(1):135–145. https://doi.org/10.1002/pro.3290", "volume": "27", "year": "2018" }, { "DOI": "10.1186/s12985-024-02365-3", "author": "N Sultana", "doi-asserted-by": "publisher", "first-page": "88", "issue": "1", "journal-title": "Virol J", "key": "446_CR49", "unstructured": "Sultana N, Nagesha SN, Reddy CL, Ramesh BN, Shyamalamma S, Shashidhara KS, Vidyadhar GD (2024) Computational analysis of affinity dynamics between the variants of SARS-CoV-2 spikes protein (RBD) and human ACE-2 receptor. Virol J 21(1):88. https://doi.org/10.1186/s12985-024-02365-3", "volume": "21", "year": "2024" }, { "DOI": "10.3389/fphar.2021.717757", "author": "TE Tallei", "doi-asserted-by": "publisher", "first-page": "717757", "journal-title": "Front Pharmacol", "key": "446_CR50", "unstructured": "Tallei TE, Fatimawali, Yelnetty A, Idroes R, Kusumawaty D, Emran TB, Celik I (2021) An analysis based on molecular docking and molecular dynamics simulation study of bromelain as anti-SARS-CoV-2 variants. Front Pharmacol 12:717757. https://doi.org/10.3389/fphar.2021.717757", "volume": "12", "year": "2021" }, { "DOI": "10.1093/molbev/msab120", "author": "K Tamura", "doi-asserted-by": "publisher", "first-page": "3022", "issue": "7", "journal-title": "Mol Biol Evol", "key": "446_CR51", "unstructured": "Tamura K, Stecher G, Kumar S (2021) MEGA11: molecular evolutionary genetics analysis version 11. Mol Biol Evol 38(7):3022–3027. https://doi.org/10.1093/molbev/msab120", "volume": "38", "year": "2021" }, { "DOI": "10.2471/BLT.22.289528", "author": "M Uludağ", "doi-asserted-by": "publisher", "first-page": "374", "issue": "6", "journal-title": "Bull World Health Organ", "key": "446_CR52", "unstructured": "Uludağ M, Incitti R, Gao X, Heeney JL, Gojobori T, Alam I (2024) Global surveillance of emerging SARS-CoV-2 variants. Bull World Health Organ 102(6):374. https://doi.org/10.2471/BLT.22.289528", "volume": "102", "year": "2024" }, { "DOI": "10.1021/acs.jctc.1c00645", "author": "MS Valdés-Tresanco", "doi-asserted-by": "publisher", "first-page": "6281", "issue": "10", "journal-title": "J Chem Theory Comput", "key": "446_CR53", "unstructured": "Valdés-Tresanco MS, Valdés-Tresanco ME, Valiente PA, Moreno E (2021) Gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS. J Chem Theory Comput 17(10):6281–6291. https://doi.org/10.1021/acs.jctc.1c00645", "volume": "17", "year": "2021" }, { "DOI": "10.21769/BioProtoc.2124", "author": "A Vangone", "doi-asserted-by": "publisher", "first-page": "e2124", "issue": "3", "journal-title": "Bio-Protoc", "key": "446_CR54", "unstructured": "Vangone A, Bonvin AM (2017) PRODIGY: a contact-based predictor of binding affinity in protein-protein complexes. Bio-Protoc 7(3):e2124–e2124. https://doi.org/10.21769/BioProtoc.2124", "volume": "7", "year": "2017" }, { "DOI": "10.3390/foods10102249", "author": "C Varilla", "doi-asserted-by": "publisher", "first-page": "2249", "issue": "10", "journal-title": "Foods", "key": "446_CR55", "unstructured": "Varilla C, Marcone M, Paiva L, Baptista J (2021) Bromelain, a group of pineapple proteolytic complex enzymes (Ananas comosus) and their possible therapeutic and clinical effects. A summary. Foods 10(10):2249. https://doi.org/10.3390/foods10102249", "volume": "10", "year": "2021" }, { "DOI": "10.1016/j.cell.2020.03.045", "author": "Q Wang", "doi-asserted-by": "publisher", "first-page": "894", "issue": "4", "journal-title": "Cell", "key": "446_CR56", "unstructured": "Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Qi J (2020) Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181(4):894–904. https://doi.org/10.1016/j.cell.2020.03.045", "volume": "181", "year": "2020" }, { "DOI": "10.1093/nar/gky427", "author": "A Waterhouse", "doi-asserted-by": "publisher", "first-page": "W296", "issue": "W1", "journal-title": "Nucleic Acids Res", "key": "446_CR58", "unstructured": "Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Schwede T (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46(W1):W296–W303. https://doi.org/10.1093/nar/gky427", "volume": "46", "year": "2018" }, { "DOI": "10.1093/bioinformatics/btp033", "author": "AM Waterhouse", "doi-asserted-by": "publisher", "first-page": "1189", "issue": "9", "journal-title": "Bioinformatics", "key": "446_CR57", "unstructured": "Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview version 2-a multiple sequence alignment editor and analysis workbench. Bioinformatics 25(9):1189–1191. https://doi.org/10.1093/bioinformatics/btp033", "volume": "25", "year": "2009" }, { "DOI": "10.1093/nar/gkm290", "author": "M Wiederstein", "doi-asserted-by": "publisher", "first-page": "W407", "issue": "suppl_2", "journal-title": "Nucleic Acids Res", "key": "446_CR59", "unstructured": "Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35(suppl_2):W407–W410. https://doi.org/10.1093/nar/gkm290", "volume": "35", "year": "2007" }, { "key": "446_CR60", "unstructured": "World Health Organization (2025) COVID-19 dashboard. WHO data. https://data.who.int/dashboards/covid19/cases. Accessed 20 Feb 2025" } ], "reference-count": 61, "references-count": 61, "relation": {}, "resource": { "primary": { "URL": "https://link.springer.com/10.1007/s40203-025-00446-x" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Targeting SARS-CoV-2 variants with Bromelain: an in-silico study of Spike-ACE2 inhibition using docking, molecular dynamic simulation, and MM-PBSA", "type": "journal-article", "update-policy": "https://doi.org/10.1007/springer_crossmark_policy", "volume": "13" }