{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:56:47Z","timestamp":1786982207614,"version":"build-2736575974"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005274","name":"North-West University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005274","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biotechnol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The Zika virus (ZIKV), an arbovirus within the Flavivirus genus, is associated with severe neurological complications, including Guillain-Barr\u00e9 syndrome in affected individuals and microcephaly in infants born to infected mothers. With no approved vaccines or antiviral treatments available, there is an urgent need for effective therapeutic options. This study aimed to identify new natural compounds with inhibitory potential against the NS2B-NS3 protease (PDB ID: 5LC0), an essential enzyme in viral replication. An e-pharmacophore model was generated using a five-point (ADDRR) feature approach in the PHASE module of Schrodinger and used for the virtual screening of 26,689 natural compounds from the PubChem database. The screening yielded 14,277 prioritized compounds based on fitness scores, further refined through extra precision (XP) docking in GLIDE, resulting in 24 compounds. Eight top hits were selected following ADME analysis with SwissADME, and toxicity screening with ProTox-II identified four non-toxic lead candidates. Molecular dynamic simulations confirmed the stability of the three most promising leads, CID 44418637, CID 163078083, and CID 68734190, with binding affinities of\u2009\u2212\u20097.721,\u2009\u2212\u20098.226, and\u2009\u2212\u20098.307\u00a0kcal\/mol, respectively. MM\/GBSA analysis revealed that Compounds 68734190 (\u2212\u200950.192\u00a0kcal\/mol) and 163078083 (\u2212\u200949.947\u00a0kcal\/mol) possess superior binding affinities to the ZIKV NS2B-NS3 protease compared to the reference compound (\u2212\u200938.347\u00a0kcal\/mol). Given their natural origin, these compounds may offer safer options to mitigate severe ZIKV-related symptoms while providing a favourable safety and pharmacokinetic profile. This study lays the groundwork for developing targeted ZIKV therapies, potentially addressing a significant unmet need in public health by reducing the incidence of ZIKV-related complications. Further experimental validation is required to confirm efficacy and address potential development challenges.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s12033-024-01357-6","type":"journal-article","created":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T13:14:58Z","timestamp":1735391698000},"page":"4632-4650","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification and Evaluation of Natural Compounds as Potential Inhibitors of NS2B-NS3 Zika Virus Protease: A Computational Approach"],"prefix":"10.1007","volume":"67","author":[{"given":"Nada","family":"Anede","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mebarka","family":"Ouassaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-7389","authenticated-orcid":false,"given":"Kannan R. R.","family":"Rengasamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafi Ullah","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader Y.","family":"Alhatlani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"key":"1357_CR1","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.tim.2017.07.001","volume":"25","author":"C Kang","year":"2017","unstructured":"Kang, C., Keller, T. H., & Luo, D. (2017). Zika virus protease: An antiviral drug target. Trends in Microbiology, 25, 797\u2013808. https:\/\/doi.org\/10.1016\/j.tim.2017.07.001","journal-title":"Trends in Microbiology"},{"key":"1357_CR2","doi-asserted-by":"publisher","unstructured":"Angel Elma, I. A., Margaret, B., Anastasia, A., Massamba, S., Laura, B. D. (224). Low humidity enhances Zika virus infection and dissemination in Aedes aegypti mosquitoes. bioRxiv. 2024.01.17.576075. https:\/\/doi.org\/10.1101\/2024.01.17.576075.","DOI":"10.1101\/2024.01.17.576075"},{"key":"1357_CR3","unstructured":"zika-epidemiology-update_february-2022_clean-version.pdf, https:\/\/cdn.who.int\/media\/docs\/default-source\/documents\/emergencies\/zika\/zika-epidemiology-update_february-2022_clean-version.pdf?sfvrsn=c4cec7b7_13&download=true."},{"key":"1357_CR4","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","volume":"46","author":"GWA Dick","year":"1952","unstructured":"Dick, G. W. A., Kitchen, S. F., & Haddow, A. J. (1952). Zika Virus (I) Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene, 46, 509\u2013520. https:\/\/doi.org\/10.1016\/0035-9203(52)90042-4","journal-title":"Transactions of the Royal Society of Tropical Medicine and Hygiene"},{"key":"1357_CR5","doi-asserted-by":"publisher","first-page":"S860","DOI":"10.1093\/infdis\/jix451","volume":"216","author":"DJ Gubler","year":"2017","unstructured":"Gubler, D. J., Vasilakis, N., & Musso, D. (2017). History and emergence of Zika virus. The Journal of Infectious Diseases, 216, S860\u2013S867. https:\/\/doi.org\/10.1093\/infdis\/jix451","journal-title":"The Journal of Infectious Diseases"},{"key":"1357_CR6","doi-asserted-by":"publisher","first-page":"50","DOI":"10.3390\/v16010050","volume":"16","author":"C Merakou","year":"2023","unstructured":"Merakou, C., Amendola, A., Fortuna, C., Marsili, G., Fiorentini, C., Argentini, C., Benedetti, E., Rezza, G., Maraglino, F., Del Manso, M., Bella, A., Pezzotti, P., Riccardo, F., Palamara, A. T., & Venturi, G. (2023). The Arbovirus Working Group: Diagnosis of imported dengue and zika virus infections in Italy from November 2015 to November 2022: Laboratory surveillance data from a national reference laboratory. Viruses, 16, 50. https:\/\/doi.org\/10.3390\/v16010050","journal-title":"Viruses"},{"key":"1357_CR7","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.ejmech.2018.07.014","volume":"156","author":"A Qadir","year":"2018","unstructured":"Qadir, A., Riaz, M., Saeed, M., & Shahzad-ul-Hussan, S. (2018). Potential targets for therapeutic intervention and structure based vaccine design against Zika virus. European Journal of Medicinal Chemistry, 156, 444\u2013460. https:\/\/doi.org\/10.1016\/j.ejmech.2018.07.014","journal-title":"European Journal of Medicinal Chemistry"},{"key":"1357_CR8","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.3201\/eid1509.090442","volume":"15","author":"EB Hayes","year":"2009","unstructured":"Hayes, E. B. (2009). Zika virus Outside Africa. Emerging Infectious Diseases, 15, 1347\u20131350. https:\/\/doi.org\/10.3201\/eid1509.090442","journal-title":"Emerging Infectious Diseases"},{"key":"1357_CR9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41594-017-0010-8","volume":"25","author":"SS Hasan","year":"2018","unstructured":"Hasan, S. S., Sevvana, M., Kuhn, R. J., & Rossmann, M. G. (2018). Structural biology of Zika virus and other flaviviruses. Nature Structural & Molecular Biology, 25, 13\u201320. https:\/\/doi.org\/10.1038\/s41594-017-0010-8","journal-title":"Nature Structural & Molecular Biology"},{"key":"1357_CR10","doi-asserted-by":"publisher","first-page":"2725","DOI":"10.3389\/fmicb.2019.02725","volume":"10","author":"L Wang","year":"2019","unstructured":"Wang, L., Liang, R., Gao, Y., Li, Y., Deng, X., Xiang, R., Zhang, Y., Ying, T., Jiang, S., & Yu, F. (2019). Development of small-molecule inhibitors against Zika Virus infection. Frontiers in Microbiology, 10, 2725. https:\/\/doi.org\/10.3389\/fmicb.2019.02725","journal-title":"Frontiers in Microbiology"},{"key":"1357_CR11","doi-asserted-by":"publisher","unstructured":"Mottin, M., Borba, J.V.V.B., Braga, R.C., Torres, P.H.M., Martini, M.C., Proenca-Modena, J.L., Judice, C.C., Costa, F.T.M., Ekins, S., Perryman, A.L., Horta Andrade, C. (2018). The A\u2013Z of Zika drug discovery. Drug Discovery Today, 23, 1833\u20131847. https:\/\/doi.org\/10.1016\/j.drudis.2018.06.014","DOI":"10.1016\/j.drudis.2018.06.014"},{"key":"1357_CR12","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.3390\/v14061226","volume":"14","author":"X Qian","year":"2022","unstructured":"Qian, X., & Qi, Z. (2022). Mosquito-borne flaviviruses and current therapeutic advances. Viruses, 14, 1226. https:\/\/doi.org\/10.3390\/v14061226","journal-title":"Viruses"},{"key":"1357_CR13","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.3390\/ph16091319","volume":"16","author":"LH Santos","year":"2023","unstructured":"Santos, L. H., Rocha, R. E. O., Dias, D. L., Ribeiro, B. M. R. M., Serafim, M. S. M., Abrah\u00e3o, J. S., & Ferreira, R. S. (2023). Evaluating known Zika Virus NS2B-NS3 protease inhibitor scaffolds via in silico screening and biochemical assays. Pharmaceuticals, 16, 1319. https:\/\/doi.org\/10.3390\/ph16091319","journal-title":"Pharmaceuticals"},{"key":"1357_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.imu.2023.101214","volume":"38","author":"DJ Gbore","year":"2023","unstructured":"Gbore, D. J., Zakari, S., & Yusuf, L. (2023). In silico studies of bioactive compounds from Alpinia officinarum as inhibitors of Zika virus protease. Informatics in Medicine Unlocked, 38, 101214. https:\/\/doi.org\/10.1016\/j.imu.2023.101214","journal-title":"Informatics in Medicine Unlocked"},{"key":"1357_CR15","doi-asserted-by":"publisher","unstructured":"Singh, S., Bani Baker, Q., & Singh, D.B. (2022). Molecular docking and molecular dynamics simulation. In: Bioinformatics. pp. 291\u2013304. Elsevier. https:\/\/doi.org\/10.1016\/B978-0-323-89775-4.00014-6.","DOI":"10.1016\/B978-0-323-89775-4.00014-6"},{"key":"1357_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.imu.2022.100880","volume":"29","author":"TI Adelusi","year":"2022","unstructured":"Adelusi, T. I., Oyedele, A.-Q.K., Boyenle, I. D., Ogunlana, A. T., Adeyemi, R. O., Ukachi, C. D., Idris, M. O., Olaoba, O. T., Adedotun, I. O., Kolawole, O. E., Xiaoxing, Y., & Abdul-Hammed, M. (2022). Molecular modeling in drug discovery. Informatics in Medicine Unlocked, 29, 100880. https:\/\/doi.org\/10.1016\/j.imu.2022.100880","journal-title":"Informatics in Medicine Unlocked"},{"key":"1357_CR17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0307902","volume":"19","author":"S Ullah","year":"2024","unstructured":"Ullah, S., Ullah, F., Rahman, W., Ullah, A., Haider, S., & Yueguang, C. (2024). Elucidating the inhibitory mechanism of Zika virus NS2B-NS3 protease with dipeptide inhibitors: Insights from molecular docking and molecular dynamics simulations. PLoS ONE, 19, e0307902. https:\/\/doi.org\/10.1371\/journal.pone.0307902","journal-title":"PLoS ONE"},{"key":"1357_CR18","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.3390\/ph17081067","volume":"17","author":"HN Altayb","year":"2024","unstructured":"Altayb, H. N., & Alatawi, H. A. (2024). Employing machine learning-based QSAR for targeting Zika Virus NS3 Protease: Molecular insights and inhibitor discovery. Pharmaceuticals., 17, 1067. https:\/\/doi.org\/10.3390\/ph17081067","journal-title":"Pharmaceuticals"},{"key":"1357_CR19","doi-asserted-by":"publisher","unstructured":"Ni, X., Godoy, A.S., Marples, P.G., Fairhead, M., Balcomb, B.H., Ferla, M.P., Tomlinson, C.W.E., Wang, S., Giroud, C., Aschenbrenner, J.C., Lithgo, R.M., Winokan, M., Chandran, A.V., Thompson, W., Xavier, M.-A., Williams, E.P., Walsh, M., Fearon, D., Koekemoer, L., & Von Delft, F. (2024). Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development. https:\/\/doi.org\/10.1101\/2024.04.29.591502.","DOI":"10.1101\/2024.04.29.591502"},{"key":"1357_CR20","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.3390\/ijms25084376","volume":"25","author":"J Starvaggi","year":"2024","unstructured":"Starvaggi, J., Previti, S., Zappal\u00e0, M., & Ettari, R. (2024). The inhibition of NS2B\/NS3 protease: A new therapeutic opportunity to treat dengue and Zika virus infection. IJMS, 25, 4376. https:\/\/doi.org\/10.3390\/ijms25084376","journal-title":"IJMS"},{"key":"1357_CR21","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1126\/science.aag2419","volume":"353","author":"J Lei","year":"2016","unstructured":"Lei, J., Hansen, G., Nitsche, C., Klein, C. D., Zhang, L., & Hilgenfeld, R. (2016). Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science, 353, 503\u2013505. https:\/\/doi.org\/10.1126\/science.aag2419","journal-title":"Science"},{"key":"1357_CR22","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.sjbs.2020.10.023","volume":"28","author":"JJ Sahayarayan","year":"2021","unstructured":"Sahayarayan, J. J., Rajan, K. S., Vidhyavathi, R., Nachiappan, M., Prabhu, D., Alfarraj, S., Arokiyaraj, S., & Daniel, A. N. (2021). In-silico protein-ligand docking studies against the estrogen protein of breast cancer using pharmacophore based virtual screening approaches. Saudi Journal of Biological Sciences, 28, 400\u2013407. https:\/\/doi.org\/10.1016\/j.sjbs.2020.10.023","journal-title":"Saudi Journal of Biological Sciences"},{"key":"1357_CR23","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1080\/07391102.2019.1709546","volume":"39","author":"R Yadav","year":"2021","unstructured":"Yadav, R., Selvaraj, C., Aarthy, M., Kumar, P., Kumar, A., Singh, S. K., & Giri, R. (2021). Investigating into the molecular interactions of flavonoids targeting NS2B-NS3 protease from ZIKA virus through in-silico approaches. Journal of Biomolecular Structure and Dynamics, 39, 272\u2013284. https:\/\/doi.org\/10.1080\/07391102.2019.1709546","journal-title":"Journal of Biomolecular Structure and Dynamics"},{"key":"1357_CR24","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s10529-016-2261-6","volume":"39","author":"H Lim","year":"2017","unstructured":"Lim, H., Nguyen, T. T. H., Kim, N. M., Park, J.-S., Jang, T.-S., & Kim, D. (2017). Inhibitory effect of flavonoids against NS2B-NS3 protease of ZIKA virus and their structure activity relationship. Biotechnology Letters, 39, 415\u2013421. https:\/\/doi.org\/10.1007\/s10529-016-2261-6","journal-title":"Biotechnology Letters"},{"key":"1357_CR25","doi-asserted-by":"publisher","unstructured":"Lima, C.S., Mottin, M., De Assis, L.R., Mesquita, N.C.D.M.R., Sousa, B.K.D.P., Coimbra, L.D., Santos, K.B.-, Zorn, K.M., Guido, R.V.C., Ekins, S., Marques, R.E., Proen\u00e7a-Modena, J.L., Oliva, G., Andrade, C.H., & Regasini, L.O. (2021). Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors. Bioorganic Chemistry, 109, 104719. https:\/\/doi.org\/10.1016\/j.bioorg.2021.104719.","DOI":"10.1016\/j.bioorg.2021.104719"},{"key":"1357_CR26","doi-asserted-by":"publisher","DOI":"10.1002\/psc.3196","volume":"25","author":"HA Rothan","year":"2019","unstructured":"Rothan, H. A., Abdulrahman, A. Y., Khazali, A. S., Nor Rashid, N., Chong, T. T., & Yusof, R. (2019). Carnosine exhibits significant antiviral activity against Dengue and Zika virus. Journal of Peptide Science, 25, e3196. https:\/\/doi.org\/10.1002\/psc.3196","journal-title":"Journal of Peptide Science"},{"key":"1357_CR27","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s12900-018-0084-5","volume":"18","author":"MW Sarwar","year":"2018","unstructured":"Sarwar, M. W., Riaz, A., Dilshad, S. M. R., Al-Qahtani, A., Nawaz-Ul-Rehman, M. S., & Mubin, M. (2018). Structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) studies showed plant flavonoids as potential inhibitors of dengue NS2B-NS3 protease. BMC Structural Biology, 18, 6. https:\/\/doi.org\/10.1186\/s12900-018-0084-5","journal-title":"BMC Structural Biology"},{"issue":"1","key":"1357_CR28","doi-asserted-by":"publisher","first-page":"54","DOI":"10.6026\/97320630009054","volume":"9","author":"C Seniya","year":"2013","unstructured":"Seniya, C., Mishra, H., Yadav, A., Sagar, N., Chaturvedi, B., Uchadia, K., & Wadhwa, G. (2013). Antiviral potential of 4-hydroxypanduratin A, secondary metabolite of Fingerroot, Boesenbergia pandurata (Schult.), towards Japanese Encephalitis virus NS2B\/NS3 protease. Bioinformation, 9(1), 54\u201360. https:\/\/doi.org\/10.6026\/97320630009054","journal-title":"Bioinformation"},{"key":"1357_CR29","doi-asserted-by":"publisher","first-page":"11203","DOI":"10.1080\/07391102.2021.1956592","volume":"40","author":"G Thirumoorthy","year":"2022","unstructured":"Thirumoorthy, G., Tarachand, S. P., Nagella, P., & Veerappa Lakshmaiah, V. (2022). Identification of potential ZIKV NS2B-NS3 protease inhibitors from Andrographis paniculata\u202f: An insilico approach. Journal of Biomolecular Structure and Dynamics, 40, 11203\u201311215. https:\/\/doi.org\/10.1080\/07391102.2021.1956592","journal-title":"Journal of Biomolecular Structure and Dynamics"},{"key":"1357_CR30","doi-asserted-by":"publisher","first-page":"13398","DOI":"10.1038\/s41598-023-40160-2","volume":"13","author":"PC Agu","year":"2023","unstructured":"Agu, P. C., Afiukwa, C. A., Orji, O. U., Ezeh, E. M., Ofoke, I. H., Ogbu, C. O., Ugwuja, E. I., & Aja, P. M. (2023). Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Science and Reports, 13, 13398. https:\/\/doi.org\/10.1038\/s41598-023-40160-2","journal-title":"Science and Reports"},{"key":"1357_CR31","doi-asserted-by":"publisher","first-page":"13384","DOI":"10.3390\/molecules200713384","volume":"20","author":"L Ferreira","year":"2015","unstructured":"Ferreira, L., Dos Santos, R., Oliva, G., & Andricopulo, A. (2015). Molecular docking and structure-based drug design strategies. Molecules, 20, 13384\u201313421. https:\/\/doi.org\/10.3390\/molecules200713384","journal-title":"Molecules"},{"key":"1357_CR32","doi-asserted-by":"publisher","first-page":"2777","DOI":"10.1021\/acs.jmedchem.0c02070","volume":"64","author":"S Nie","year":"2021","unstructured":"Nie, S., Yao, Y., Wu, F., Wu, X., Zhao, J., Hua, Y., Wu, J., Huo, T., Lin, Y.-L., Kneubehl, A. R., Vogt, M. B., Ferreon, J., Rico-Hesse, R., & Song, Y. (2021). Synthesis, structure-activity relationships, and antiviral activity of allosteric inhibitors of Flavivirus NS2B\u2013NS3 protease. Journal of Medicinal Chemistry, 64, 2777\u20132800. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c02070","journal-title":"Journal of Medicinal Chemistry"},{"key":"1357_CR33","doi-asserted-by":"publisher","unstructured":"Rehman, H. M., Sajjad, M., Ali, M. A., Gul, R., Irfan, M., Naveed, M., Bhinder, M. A., Ghani, M. U., Hussain, N., Said, A. S. A., Al Haddad, A. H. I., & Saleem, M. (2023). Identification of NS2B-NS3 protease inhibitors for therapeutic application in ZIKV Infection: A pharmacophore-based high-throughput virtual screening and MD simulations approaches. Vaccines, 11, 131. https:\/\/doi.org\/10.3390\/vaccines11010131.","DOI":"10.3390\/vaccines11010131"},{"key":"1357_CR34","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s12010-018-2814-3","volume":"187","author":"K Rohini","year":"2019","unstructured":"Rohini, K., Agarwal, P., Preethi, B., Shanthi, V., & Ramanathan, K. (2019). Exploring the lead compounds for Zika Virus NS2B-NS3 Protein: An e-pharmacophore-based approach. Applied Biochemistry and Biotechnology, 187, 194\u2013210. https:\/\/doi.org\/10.1007\/s12010-018-2814-3","journal-title":"Applied Biochemistry and Biotechnology"},{"key":"1357_CR35","doi-asserted-by":"publisher","first-page":"558","DOI":"10.3109\/10799893.2016.1141955","volume":"36","author":"SK Katari","year":"2016","unstructured":"Katari, S. K., Natarajan, P., Swargam, S., Kanipakam, H., Pasala, C., & Umamaheswari, A. (2016). Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations. Journal of Receptors and Signal Transduction, 36, 558\u2013571. https:\/\/doi.org\/10.3109\/10799893.2016.1141955","journal-title":"Journal of Receptors and Signal Transduction"},{"key":"1357_CR36","doi-asserted-by":"publisher","unstructured":"Mandlik, V., Bejugam, P. R., & Singh, S. (2016). Application of Artificial Neural Networks in Modern Drug Discovery. In: Artificial Neural Network for Drug Design, Delivery and Disposition. pp. 123\u2013139. Elsevier. https:\/\/doi.org\/10.1016\/B978-0-12-801559-9.00006-5.","DOI":"10.1016\/B978-0-12-801559-9.00006-5"},{"key":"1357_CR37","doi-asserted-by":"publisher","first-page":"4908","DOI":"10.1038\/s41598-023-31169-8","volume":"13","author":"B Sharma","year":"2023","unstructured":"Sharma, B., Chenthamarakshan, V., Dhurandhar, A., Pereira, S., Hendler, J. A., Dordick, J. S., & Das, P. (2023). Accurate clinical toxicity prediction using multi-task deep neural nets and contrastive molecular explanations. Science and Reports, 13, 4908. https:\/\/doi.org\/10.1038\/s41598-023-31169-8","journal-title":"Science and Reports"},{"key":"1357_CR38","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1002\/jcc.20292","volume":"26","author":"JL Banks","year":"2005","unstructured":"Banks, J. L., Beard, H. S., Cao, Y., Cho, A. E., Damm, W., Farid, R., Felts, A. K., Halgren, T. A., Mainz, D. T., Maple, J. R., Murphy, R., Philipp, D. M., Repasky, M. P., Zhang, L. Y., Berne, B. J., Friesner, R. A., Gallicchio, E., & Levy, R. M. (2005). Integrated modeling program, applied chemical theory (IMPACT). Journal of Computational Chemistry, 26, 1752\u20131780. https:\/\/doi.org\/10.1002\/jcc.20292","journal-title":"Journal of Computational Chemistry"},{"key":"1357_CR39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0010-4655(96)00016-1","volume":"95","author":"AY Toukmaji","year":"1996","unstructured":"Toukmaji, A. Y., & Board, J. A. (1996). Ewald summation techniques in perspective: A survey. Computer Physics Communications, 95, 73\u201392. https:\/\/doi.org\/10.1016\/0010-4655(96)00016-1","journal-title":"Computer Physics Communications"},{"key":"1357_CR40","doi-asserted-by":"publisher","DOI":"10.1063\/1.2018637","volume":"123","author":"J Zielkiewicz","year":"2005","unstructured":"Zielkiewicz, J. (2005). Structural properties of water: Comparison of the SPC, SPCE, TIP4P, and TIP5P models of water. The Journal of Chemical Physics, 123, 104501. https:\/\/doi.org\/10.1063\/1.2018637","journal-title":"The Journal of Chemical Physics"},{"key":"1357_CR41","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.1063\/1.463940","volume":"97","author":"GJ Martyna","year":"1992","unstructured":"Martyna, G. J., Klein, M. L., & Tuckerman, M. (1992). Nos\u00e9-Hoover chains: The canonical ensemble via continuous dynamics. The Journal of Chemical Physics, 97, 2635\u20132643. https:\/\/doi.org\/10.1063\/1.463940","journal-title":"The Journal of Chemical Physics"},{"key":"1357_CR42","doi-asserted-by":"publisher","first-page":"3659","DOI":"10.1021\/acs.jcim.1c00135","volume":"61","author":"AFA Moumbock","year":"2021","unstructured":"Moumbock, A. F. A., Li, J., Tran, H. T. T., Hinkelmann, R., Lamy, E., Jessen, H. J., & G\u00fcnther, S. (2021). ePharmaLib: A versatile library of e-Pharmacophores to address small-molecule (Poly-)pharmacology. Journal of Chemical Information and Modeling, 61, 3659\u20133666. https:\/\/doi.org\/10.1021\/acs.jcim.1c00135","journal-title":"Journal of Chemical Information and Modeling"},{"key":"1357_CR43","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1021\/ci600426e","volume":"47","author":"J-F Truchon","year":"2007","unstructured":"Truchon, J.-F., & Bayly, C. I. (2007). Evaluating virtual screening methods: Good and bad metrics for the \u201cEarly Recognition\u201d problem. Journal of Chemical Information and Modeling, 47, 488\u2013508. https:\/\/doi.org\/10.1021\/ci600426e","journal-title":"Journal of Chemical Information and Modeling"},{"key":"1357_CR44","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/1471-2105-10-225","volume":"10","author":"W Zhao","year":"2009","unstructured":"Zhao, W., Hevener, K. E., White, S. W., Lee, R. E., & Boyett, J. M. (2009). A statistical framework to evaluate virtual screening. BMC Bioinformatics, 10, 225. https:\/\/doi.org\/10.1186\/1471-2105-10-225","journal-title":"BMC Bioinformatics"},{"key":"1357_CR45","doi-asserted-by":"publisher","unstructured":"McREE, D.E.: COMPUTATIONAL TECHNIQUES. In: Practical Protein Crystallography. pp. 91-cp1. Elsevier (1999). https:\/\/doi.org\/10.1016\/B978-012486052-0\/50005-1.","DOI":"10.1016\/B978-012486052-0\/50005-1"},{"key":"1357_CR46","doi-asserted-by":"publisher","unstructured":"Chandrasekaran, B., Abed, S. N., Al-Attraqchi, O., Kuche, K., Tekade, R. K. (2018). Computer-aided prediction of pharmacokinetic (ADMET) properties. In: Dosage Form Design Parameters. pp. 731\u2013755. Elsevier. https:\/\/doi.org\/10.1016\/B978-0-12-814421-3.00021-X.","DOI":"10.1016\/B978-0-12-814421-3.00021-X"},{"key":"1357_CR47","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","volume":"1","author":"CA Lipinski","year":"2004","unstructured":"Lipinski, C. A. (2004). Lead- and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies, 1, 337\u2013341. https:\/\/doi.org\/10.1016\/j.ddtec.2004.11.007","journal-title":"Drug Discovery Today: Technologies"},{"key":"1357_CR48","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1021\/jm020017n","volume":"45","author":"DF Veber","year":"2002","unstructured":"Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002). Molecular properties that influence the oral bioavailability of drug candidates. Journal of Medicinal Chemistry, 45, 2615\u20132623. https:\/\/doi.org\/10.1021\/jm020017n","journal-title":"Journal of Medicinal Chemistry"},{"key":"1357_CR49","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/wics.1310","volume":"6","author":"S Chow","year":"2014","unstructured":"Chow, S. (2014). Bioavailability and bioequivalence in drug development. WIREs Computational Stats, 6, 304\u2013312. https:\/\/doi.org\/10.1002\/wics.1310","journal-title":"WIREs Computational Stats"},{"key":"1357_CR50","doi-asserted-by":"publisher","first-page":"11264","DOI":"10.1080\/07391102.2021.1957712","volume":"40","author":"M Ouassaf","year":"2022","unstructured":"Ouassaf, M., Belaidi, S., Chtita, S., Lanez, T., Abul Qais, F., & Md Amiruddin, H. (2022). Combined molecular docking and dynamics simulations studies of natural compounds as potent inhibitors against SARS-CoV-2 main protease. Journal of Biomolecular Structure and Dynamics, 40, 11264\u201311273. https:\/\/doi.org\/10.1080\/07391102.2021.1957712","journal-title":"Journal of Biomolecular Structure and Dynamics"},{"key":"1357_CR51","doi-asserted-by":"publisher","first-page":"12808","DOI":"10.3390\/ijms222312808","volume":"22","author":"M Zhao","year":"2021","unstructured":"Zhao, M., Ma, J., Li, M., Zhang, Y., Jiang, B., Zhao, X., Huai, C., Shen, L., Zhang, N., He, L., & Qin, S. (2021). Cytochrome P450 enzymes and drug metabolism in humans. IJMS., 22, 12808. https:\/\/doi.org\/10.3390\/ijms222312808","journal-title":"IJMS."},{"key":"1357_CR52","doi-asserted-by":"publisher","unstructured":"Ouassaf, M., Belaidi, S., Mogren Al Mogren, M., Chtita, S., Ullah Khan, S., & Thet Htar, T. (2021). Combined docking methods and molecular dynamics to identify effective antiviral 2, 5-diaminobenzophenonederivatives against SARS-CoV-2. Journal of King Saud University - Science, 33, 101352. https:\/\/doi.org\/10.1016\/j.jksus.2021.101352.","DOI":"10.1016\/j.jksus.2021.101352"},{"key":"1357_CR53","doi-asserted-by":"publisher","unstructured":"Rubinchik-Stern, M., & Eyal, S. (2012). Drug Interactions at the Human Placenta: What is the Evidence? Frontiers of Pharmacology 3,. https:\/\/doi.org\/10.3389\/fphar.2012.00126.","DOI":"10.3389\/fphar.2012.00126"},{"key":"1357_CR54","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1758-2946-1-8","volume":"1","author":"P Ertl","year":"2009","unstructured":"Ertl, P., & Schuffenhauer, A. (2009). Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. Journal of Cheminformatics, 1, 8. https:\/\/doi.org\/10.1186\/1758-2946-1-8","journal-title":"Journal of Cheminformatics"},{"key":"1357_CR55","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13321-023-00678-z","volume":"15","author":"G Skoraczy\u0144ski","year":"2023","unstructured":"Skoraczy\u0144ski, G., Kitlas, M., Miasojedow, B., & Gambin, A. (2023). Critical assessment of synthetic accessibility scores in computer-assisted synthesis planning. Journal of Cheminformatics, 15, 6. https:\/\/doi.org\/10.1186\/s13321-023-00678-z","journal-title":"Journal of Cheminformatics"},{"key":"1357_CR56","doi-asserted-by":"publisher","unstructured":"Tang, Z., & Zhang, Q. (2022). The potential toxic side effects of flavonoids. BIOCELL, 46, 357\u2013366. https:\/\/doi.org\/10.32604\/biocell.2022.015958.","DOI":"10.32604\/biocell.2022.015958"},{"key":"1357_CR57","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41392-022-00904-4","volume":"7","author":"L Wang","year":"2022","unstructured":"Wang, L., Wang, N., Zhang, W., Cheng, X., Yan, Z., Shao, G., Wang, X., Wang, R., & Fu, C. (2022). Therapeutic peptides: Current applications and future directions. Signal Transduction and Targeted Therapy, 7, 48. https:\/\/doi.org\/10.1038\/s41392-022-00904-4","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"1357_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111596","volume":"140","author":"SL Badshah","year":"2021","unstructured":"Badshah, S. L., Faisal, S., Muhammad, A., Poulson, B. G., Emwas, A. H., & Jaremko, M. (2021). Antiviral activities of flavonoids. Biomedicine & Pharmacotherapy, 140, 111596. https:\/\/doi.org\/10.1016\/j.biopha.2021.111596","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"1357_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2023.106792","volume":"61","author":"R Ce\u00f1a-Diez","year":"2023","unstructured":"Ce\u00f1a-Diez, R., Narayanan, A., Ray, S., Van De Klundert, M., Rodriguez, J. E., Nilvebrant, J., Nygren, P. -\u00c5., V\u00e9gv\u00e1ri, \u00c1., Van Domselaar, R., & S\u00f6nnerborg, A. (2023). Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism. International Journal of Antimicrobial Agents, 61, 106792. https:\/\/doi.org\/10.1016\/j.ijantimicag.2023.106792","journal-title":"International Journal of Antimicrobial Agents"},{"key":"1357_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2023.100955","volume":"68","author":"R Ce\u00f1a-Diez","year":"2023","unstructured":"Ce\u00f1a-Diez, R., Spetz, A.-L., & S\u00f6nnerborg, A. (2023). Synergistic antiviral activity against drug-resistant HIV-1 by naturally occurring dipeptide and A single-stranded oligonucleotide. Drug Resistance Updates, 68, 100955. https:\/\/doi.org\/10.1016\/j.drup.2023.100955","journal-title":"Drug Resistance Updates"},{"key":"1357_CR61","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165878","volume":"1866","author":"AAT Naqvi","year":"2020","unstructured":"Naqvi, A. A. T., Fatima, K., Mohammad, T., Fatima, U., Singh, I. K., Singh, A., Atif, S. M., Hariprasad, G., Hasan, G. M., & Hassan, Md. I. (2020). Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochimica et Biophysica Acta, Molecular Basis of Disease, 1866, 165878. https:\/\/doi.org\/10.1016\/j.bbadis.2020.165878","journal-title":"Biochimica et Biophysica Acta, Molecular Basis of Disease"}],"container-title":["Molecular Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12033-024-01357-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12033-024-01357-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12033-024-01357-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T05:12:49Z","timestamp":1763615569000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12033-024-01357-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,28]]},"references-count":61,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["1357"],"URL":"https:\/\/doi.org\/10.1007\/s12033-024-01357-6","relation":{},"ISSN":["1073-6085","1559-0305"],"issn-type":[{"value":"1073-6085","type":"print"},{"value":"1559-0305","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,28]]},"assertion":[{"value":"26 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}