{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:08:35Z","timestamp":1790003315029,"version":"4.0.1"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"TUBITAK 2236 CoCirculation2 program","doi-asserted-by":"publisher","award":["121C063"],"award-info":[{"award-number":["121C063"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The HIV-1 Gag protein binds to the host cell membrane and assembles into immature particles. Then, in the course of immature virion budding, activated protease cleaves Gag into its main components: MA, CA, NC, and p6 proteins. The highly basic residues of MA predominantly interact with the acidic head of phosphatidyl-inositol-4,5-bisphosphate (PI(4,5)P2) inserted into the membrane. Our research group developed L-Heptanoylphosphatidyl Inositol Pentakisphosphate (L-HIPPO) and previously confirmed that this compound bound to the MA more strongly than PI(4,5)P2 and inositol hexakisphosphate (IP6) did. Therefore, herein we rationally designed eight new L-HIPPO derivatives based on the fact that the most changeable parts of L-HIPPO were two acyl chains. After that, we employed molecular docking for eight compounds via Maestro software using high-resolution crystal structures of MA in complex with IP6 (PDB IDs: 7E1I, 7E1J, and 7E1K), which were recently elucidated by our research group. The most promising docking scores were obtained with benzene-inserted compounds. Thus, we generated a library containing 213 new aromatic group-inserted L-HIPPO derivatives and performed the same molecular docking procedure. According to the results, we determined the nine new L-HIPPO derivatives most effectively binding to the MA with the most favorable scoring functions and pharmacokinetic properties for further exploration.<\/jats:p>","DOI":"10.3390\/ph15101255","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T22:45:29Z","timestamp":1665614729000},"page":"1255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of New L-Heptanoylphosphatidyl Inositol Pentakisphosphate Derivatives Targeting the Interaction with HIV-1 Gag by Molecular Modelling Studies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9796-7669","authenticated-orcid":false,"given":"Halilibrahim","family":"Ciftci","sequence":"first","affiliation":[{"name":"Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan"},{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"},{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4847-9711","authenticated-orcid":false,"given":"Belgin","family":"Sever","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"Ayan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Can","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"},{"name":"Department of Engineering Sciences, Faculty of Engineering and Architecture, Izmir Katip Celebi University, Izmir 35620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9135-5397","authenticated-orcid":false,"given":"Hasan","family":"DeMirci","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan"},{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5698-1109","authenticated-orcid":false,"given":"Ama\u00e7 Fatih","family":"TuYuN","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Istanbul University, Istanbul 34126, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-0720","authenticated-orcid":false,"given":"Hiroshi","family":"Tateishi","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-4052","authenticated-orcid":false,"given":"Mikako","family":"Fujita","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1517\/14728220903039714","article-title":"Virus maturation as a new HIV-1 therapeutic target","volume":"13","author":"Adamson","year":"2009","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_2","unstructured":"Elinder, M. (2011). Towards a New Generation of Anti-HIV Drugs: Interaction Kinetic Analysis of Enzyme Inhibitors Using SPR-biosensors. [Ph.D. Thesis, Acta Universitatis Upsaliensis]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1742-4690-8-15","article-title":"Retroviral matrix and lipids, the intimate interaction","volume":"8","author":"Muriaux","year":"2011","journal-title":"Retrovirology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fmicb.2012.00055","article-title":"Role of the HIV-1 Matrix Protein in Gag Intracellular Trafficking and Targeting to the Plasma Membrane for Virus Assembly","volume":"3","author":"Ghanam","year":"2012","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.tim.2014.04.012","article-title":"The role of matrix in HIV-1 envelope glycoprotein incorporation","volume":"22","author":"Tedbury","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a007161","DOI":"10.1101\/cshperspect.a007161","article-title":"HIV-1 antiretroviral drug therapy","volume":"2","author":"Arts","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/S0005-2736(03)00163-9","article-title":"Role of HIV-1 Gag domains in viral assembly","volume":"1614","author":"Scarlata","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1021\/acs.biochem.6b00159","article-title":"HIV Capsid Assembly, Mechanism, and Structure","volume":"55","author":"Chen","year":"2016","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11090","DOI":"10.1073\/pnas.0903535106","article-title":"Structure and assembly of immature HIV","volume":"106","author":"Briggs","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01079-19","DOI":"10.1128\/JVI.01079-19","article-title":"Analysis of HIV-1 Matrix-Envelope Cytoplasmic Tail Interactions","volume":"93","author":"Alfadhli","year":"2019","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1146\/annurev-virology-031413-085427","article-title":"In Vitro Assembly of Retroviruses","volume":"1","author":"Bush","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.virusres.2014.07.001","article-title":"How HIV-1 Gag assembles in cells: Putting together pieces of the puzzle","volume":"193","author":"Lingappa","year":"2014","journal-title":"Virus Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.chom.2013.08.012","article-title":"Virus budding and the ESCRT pathway","volume":"14","author":"Votteler","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"a006924","DOI":"10.1101\/cshperspect.a006924","article-title":"HIV-1 assembly, budding, and maturation","volume":"2","author":"Sundquist","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.jmb.2006.10.073","article-title":"Conformation of the HIV-1 Gag protein in solution","volume":"365","author":"Datta","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.jmb.2006.10.072","article-title":"Interactions between HIV-1 Gag molecules in solution: An inositol phosphate-mediated switch","volume":"365","author":"Datta","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1073\/pnas.0305665101","article-title":"Entropic switch regulates myristate exposure in the HIV-1 matrix protein","volume":"101","author":"Tang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1073\/pnas.0308043101","article-title":"A myristoyl switch regulates membrane binding of HIV-1 Gag","volume":"101","author":"Resh","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1128\/JVI.01809-10","article-title":"Matrix domain modulates HIV-1 Gag\u2019s nucleic acid chaperone activity via inositol phosphate binding","volume":"85","author":"Jones","year":"2011","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3389\/fmicb.2014.00187","article-title":"Membrane interaction of retroviral Gag proteins","volume":"5","author":"Dick","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19114","DOI":"10.1073\/pnas.0907364106","article-title":"Imaging the interaction of HIV-1 genomes and Gag during assembly of individual viral particles","volume":"106","author":"Jouvenet","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3374","DOI":"10.1073\/pnas.1501985112","article-title":"Conformation and dynamics of the Gag polyprotein of the human immunodeficiency virus 1 studied by NMR spectroscopy","volume":"112","author":"Deshmuk","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14889","DOI":"10.1073\/pnas.0405596101","article-title":"Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane","volume":"101","author":"Ono","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11364","DOI":"10.1073\/pnas.0602818103","article-title":"Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly","volume":"103","author":"Saad","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1128\/JVI.01614-07","article-title":"Interaction between the human immunodeficiency virus type 1 Gag matrix domain and phosphatidylinositol-(4,5)-bisphosphate is essential for efficient gag membrane binding","volume":"82","author":"Chukkapalli","year":"2008","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12196","DOI":"10.1128\/JVI.01197-09","article-title":"Analysis of human immunodeficiency virus type 1 matrix binding to membranes and nucleic acids","volume":"83","author":"Alfadhli","year":"2009","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6434","DOI":"10.1128\/JVI.02757-06","article-title":"Electrostatic interactions drive membrane association of the human immunodeficiency virus type 1 Gag MA domain","volume":"81","author":"Dalton","year":"2007","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.sbi.2008.02.001","article-title":"The structural biology of HIV assembly","volume":"18","author":"Yeager","year":"2008","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bpj.2013.12.019","article-title":"Coarse-grained simulations of the HIV-1 matrix protein anchoring: Revisiting its assembly on membrane domains","volume":"106","author":"Charlier","year":"2014","journal-title":"Biophys. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5109","DOI":"10.1021\/bi9019274","article-title":"Highly sensitive analysis of the interaction between HIV-1 Gag and phosphoinositide derivatives based on surface plasmon resonance","volume":"49","author":"Anraku","year":"2010","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10875","DOI":"10.1073\/pnas.191224698","article-title":"Modulation of HIV-like particle assembly in vitro by inositol phosphates","volume":"98","author":"Campbell","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41586-018-0396-4","article-title":"Inositol phosphates are assembly co-factors for HIV-1","volume":"560","author":"Dick","year":"2018","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e35335","DOI":"10.7554\/eLife.35335","article-title":"IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis","volume":"7","author":"Mallery","year":"2018","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1016\/j.celrep.2019.11.050","article-title":"Cellular IP6 Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP6 Are Attenuated for Infection and Replication","volume":"29","author":"Mallery","year":"2019","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e02820-20","DOI":"10.1128\/mBio.02820-20","article-title":"The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid","volume":"11","author":"Jennings","year":"2020","journal-title":"mBio"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Rica\u00f1a, C.L., and Dick, R.A. (2021). Inositol Phosphates and Retroviral Assembly: A Cellular Perspective. Viruses, 13.","DOI":"10.3390\/v13122516"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sowd, G.A., and Aiken, C. (2021). Inositol phosphates promote HIV-1 assembly and maturation to facilitate viral spread in human CD4+ T cells. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009389"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5006","DOI":"10.1039\/C4OB00350K","article-title":"Design and synthesis of lipid-coupled inositol 1,2,3,4,5,6-hexakisphosphate derivatives exhibiting high-affinity binding for the HIV-1 MA domain","volume":"12","author":"Tateishi","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/S0140-6736(20)30264-6","article-title":"Kick and kill for HIV latency","volume":"395","author":"Lewin","year":"2020","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.coviro.2016.02.001","article-title":"Which therapeutic strategy will achieve a cure for HIV-1?","volume":"18","author":"Cillo","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1080\/14787210.2019.1617697","article-title":"Curing HIV by \u2018kick and kill\u2019: From theory to practice?","volume":"17","author":"Pace","year":"2019","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41467-021-27647-0","article-title":"Latency reversal plus natural killer cells diminish HIV reservoir in vivo","volume":"13","author":"Kim","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8957","DOI":"10.1038\/s41598-017-09129-w","article-title":"A clue to unprecedented strategy to HIV eradication: \u201cLock-in and apoptosis\u201d","volume":"7","author":"Tateishi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15819","DOI":"10.1038\/s41598-021-95236-8","article-title":"Structural insight into host plasma membrane association and assembly of HIV-1 matrix protein","volume":"11","author":"Ciftci","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ciftci, H.I., Sierra, R.G., Yoon, C.H., Su, Z., Tateishi, H., Koga, R., Kotaro, K., Yumoto, F., Senda, T., and Liang, M. (2019). Serial Femtosecond X-Ray Diffraction of HIV-1 Gag MA-IP6 Microcrystals at Ambient Temperature. Int. J. Mol. Sci., 20.","DOI":"10.1101\/561100"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13321-017-0202-6","article-title":"Adverse drug reactions triggered by the common HLA-B*57:01 variant: A molecular docking study","volume":"9","author":"Fourches","year":"2017","journal-title":"J. Cheminform."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1023\/A:1007996124545","article-title":"Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes","volume":"11","author":"Eldridge","year":"1997","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/1439-7633(20020703)3:7<604::AID-CBIC604>3.0.CO;2-X","article-title":"Close-range electrostatic interactions in proteins","volume":"3","author":"Kumar","year":"2002","journal-title":"Chembiochem"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6561","DOI":"10.1021\/jp500958r","article-title":"Evaluating the strength of salt bridges: A comparison of current biomolecular force fields","volume":"118","author":"Debiec","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1021\/acs.jmedchem.7b00101","article-title":"Large-Scale Analysis of Hydrogen Bond Interaction Patterns in Protein-Ligand Interfaces","volume":"60","author":"Nittinger","year":"2017","journal-title":"Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Pantsar, T., and Poso, A. (2018). Binding Affinity via Docking: Fact and Fiction. Molecules, 23.","DOI":"10.3390\/molecules23081899"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1021\/acschemneuro.1c00229","article-title":"Docking Screens of Noncovalent Interaction Motifs of the Human Subtype-D2 Receptor-75 Schizophrenia Antipsychotic Complexes with Physicochemical Appraisal of Antipsychotics","volume":"12","author":"Amani","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Beak, M., Park, S., Kim, J.H., Eom, H.J., Lee, H.Y., Kim, Y.H., Lee, J., and Nam, S. (2022). Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer. Cancers, 14.","DOI":"10.3390\/cancers14071604"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/s00705-019-04153-9","article-title":"Examining pharmacodynamic and pharmacokinetic properties of eleven analogues of saquinavir for HIV protease inhibition","volume":"164","author":"Jayaswal","year":"2019","journal-title":"Arch. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.drudis.2019.03.013","article-title":"New targets for HIV drug discovery","volume":"24","author":"Puhl","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.tins.2020.06.007","article-title":"The Paradox of HIV Blood-Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies","volume":"43","author":"Osborne","year":"2020","journal-title":"Trends Neurosci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/10\/1255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:52:44Z","timestamp":1760143964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/10\/1255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,12]]},"references-count":56,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ph15101255"],"URL":"https:\/\/doi.org\/10.3390\/ph15101255","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,12]]}}}