{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:12:46Z","timestamp":1765807966317,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T00:00:00Z","timestamp":1635638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/ASP-AGR\/30154\/2017 (POCI-01-0145-FEDER-030154)","CQ-UM (UID\/QUI\/00686\/2020), CF-UM-UP (UIDB\/04650\/2020) and REQUIMTE (UIDB\/50006\/2020); REDE\/1517\/RMN\/2005"],"award-info":[{"award-number":["PTDC\/ASP-AGR\/30154\/2017 (POCI-01-0145-FEDER-030154)","CQ-UM (UID\/QUI\/00686\/2020), CF-UM-UP (UIDB\/04650\/2020) and REQUIMTE (UIDB\/50006\/2020); REDE\/1517\/RMN\/2005"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A series of \u03b2-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and\/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC\/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures.<\/jats:p>","DOI":"10.3390\/molecules26216616","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:22:24Z","timestamp":1635805344000},"page":"6616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Amino Alcohols from Eugenol as Potential Semisynthetic Insecticides: Chemical, Biological, and Computational Insights"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-7364","authenticated-orcid":false,"given":"Renato B.","family":"Pereira","sequence":"first","affiliation":[{"name":"REQUIMTE\/LAQV, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, R. Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"given":"Nuno F. S.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Centre of Chemistry, Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]},{"given":"Maria Jos\u00e9 G.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Centre of Chemistry, Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5137-0798","authenticated-orcid":false,"given":"Tatiana F.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, BioSIM\u2014Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-1713","authenticated-orcid":false,"given":"Ana Rita O.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Centre of Physics of Minho and Porto Universities (CF-UM-UP), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-7592","authenticated-orcid":false,"given":"David M.","family":"Pereira","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, R. Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"given":"S\u00e9rgio F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, BioSIM\u2014Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-6081","authenticated-orcid":false,"given":"Elisabete M. S.","family":"Castanheira","sequence":"additional","affiliation":[{"name":"Centre of Physics of Minho and Porto Universities (CF-UM-UP), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]},{"given":"A. Gil","family":"Fortes","sequence":"additional","affiliation":[{"name":"Centre of Chemistry, Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-1190","authenticated-orcid":false,"given":"M. Sameiro T.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Centre of Chemistry, Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.actatropica.2019.01.019","article-title":"Plant extracts for developing mosquito larvicides: From laboratory to the field, with insights on the modes of action","volume":"193","author":"Pavela","year":"2019","journal-title":"Acta Trop."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109178","DOI":"10.1016\/j.vetpar.2020.109178","article-title":"Repellent and acaricidal activity of essential oils and their components against Rhipicephalus ticks in cattle","volume":"283","author":"Salman","year":"2020","journal-title":"Vet. Parasitol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3923\/jest.2016.354.378","article-title":"Green pesticides: Essential oils as biopesticides in insect-pest management","volume":"9","author":"Mossa","year":"2016","journal-title":"J. Environ. Sci. Technol."},{"key":"ref_4","first-page":"52","article-title":"A review on prospects of essential oils as biopesticide in insect-pest management","volume":"1","author":"Tripathi","year":"2009","journal-title":"J. Pharm. Phytother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/S2221-1691(14)60215-X","article-title":"Clove (Syzygium aromaticum): A precious spice","volume":"4","year":"2014","journal-title":"Asian Pac. J. Trop. Biomed."},{"key":"ref_6","first-page":"2231","article-title":"Antimicrobial activity of eugenol derivatives","volume":"1","author":"Evambe","year":"2011","journal-title":"Heterocycl. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.nbt.2016.01.001","article-title":"Eugenol confers resistance to tomato yellow leaf curl virus (TYLCV) by regulating the expression of SlPer1 in tomato plants","volume":"33","author":"Sun","year":"2016","journal-title":"New Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.intimp.2016.06.005","article-title":"Ortho-eugenol exhibits anti-nociceptive and anti-inflammatory activities","volume":"38","author":"Fonseca","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_9","first-page":"215","article-title":"Eugenol derivatives as future potential drugs","volume":"1","author":"Awasthi","year":"2008","journal-title":"Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/arch.20076","article-title":"Molecular and pharmacological analysis of an octopamine receptor from American cockroach and fruit fly in response to plant essential oils","volume":"59","author":"Enan","year":"2005","journal-title":"Arch. Insect Biochem. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13065-018-0407-4","article-title":"Eugenol derivatives: Synthesis, characterization, and evaluation of antibacterial and antioxidant activities","volume":"12","author":"Silva","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1002\/(SICI)1521-3773(19990712)38:13\/14<1931::AID-ANIE1931>3.0.CO;2-4","article-title":"re- and si-Face-selective nitroaldol reactions catalyzed by a rigid chiral quaternary ammonium salt: A highly stereoselective synthesis of the HIV protease inhibitor amprenavir (Vertex 478)","volume":"38","author":"Corey","year":"1999","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1021\/cr9500038","article-title":"1,2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries in asymmetric synthesis","volume":"96","author":"Ager","year":"1996","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/(SICI)1521-3773(19990201)38:3<326::AID-ANIE326>3.0.CO;2-T","article-title":"Sharpless asymmetric aminohydroxylation: Scope, limitations, and use in synthesis","volume":"38","year":"1999","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/anie.199604511","article-title":"Catalytic asymmetric aminohydroxylation (AA) of olefins","volume":"35","author":"Li","year":"1996","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_16","first-page":"639","article-title":"Synthesis, antibacterial and antitubercular evaluation of cardanol and glycerol based \u03b2-amino alcohol derivatives","volume":"29","author":"Manda","year":"2018","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1016\/j.tet.2016.04.083","article-title":"Synthesis of \u03b2-amino alcohols using the tandem reduction and ring-opening reaction of nitroarenes and epoxides","volume":"72","author":"Shi","year":"2016","journal-title":"Tetrahedron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"A74","DOI":"10.1186\/1824-7288-41-S2-A74","article-title":"Salbutamol and around","volume":"41","author":"Ullmann","year":"2015","journal-title":"Ital. J. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/j.bmcl.2014.02.025","article-title":"Discovery of novel bis-oxazolidinone compounds as potential potent and selective antitubercular agents","volume":"24","author":"Ang","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7808","DOI":"10.1002\/chem.201500210","article-title":"One-pot synthesis of N-substituted \u03b2-amino alcohols from aldehydes and isocyanides","volume":"21","author":"Cioc","year":"2015","journal-title":"Chem. Eur. J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lopes, A.I.F., Monteiro, M., Ara\u00fajo, A.R.L., Rodrigues, A.R.O., Castanheira, E.M.S., Pereira, D.M., Olim, P., Fortes, A.G., and Gon\u00e7alves, M.S.T. (2020). Cytotoxic plant extracts towards insect cells: Bioactivity and nanoencapsulation studies for application as biopesticides. Molecules, 25.","DOI":"10.3390\/molecules25245855"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Fernandes, M.J.G., Pereira, R.B., Pereira, D.M., Fortes, A.G., Castanheira, E.M.S., and Gon\u00e7alves, M.S.T. (2020). New eugenol derivatives with enhanced insecticidal activity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239257"},{"key":"ref_23","first-page":"239","article-title":"Thermotropic phase transitions of pure lipids in model membranes and their modifications by membrane proteins","volume":"2","author":"Silvius","year":"1982","journal-title":"Lipid-Protein Interact."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.mtcomm.2017.03.005","article-title":"Antibacterial and antioxidant photoinitiated epoxy co-networks of resorcinol and eugenol derivatives","volume":"12","author":"Modjinou","year":"2017","journal-title":"Mater. Today Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1021\/ol051220q","article-title":"Highly chemoselective addition of amines to epoxides in water","volume":"7","author":"Azizi","year":"2015","journal-title":"Org. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1128\/IAI.73.4.1907-1916.2005","article-title":"Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells","volume":"73","author":"Fink","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"495","DOI":"10.2174\/138945012799499712","article-title":"Can acetylcholinesterase serve as a target for developing more selective insecticides?","volume":"13","author":"Lang","year":"2012","journal-title":"Curr. Drug Targets."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ibmb.2011.10.005","article-title":"Crystal structure of Apis mellifera OBP14, a C-minus odorant-binding protein, and its complexes with odorant molecules","volume":"42","author":"Spinelli","year":"2012","journal-title":"Insect Biochem. Mol. Bio."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1093\/jisesa\/iew008","article-title":"Virtual screening of plant volatile compounds reveals a high affinity of Hylamorpha elegans (Coleoptera: Scarabaeidae) odorant-binding proteins for sesquiterpenes from Its native host","volume":"16","author":"Rojas","year":"2016","journal-title":"J. Insect Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"180208","DOI":"10.1098\/rsob.180208","article-title":"The diverse small proteins called odorant-binding proteins","volume":"8","author":"Sun","year":"2018","journal-title":"Open Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/brv.12339","article-title":"Beyond chemoreception: Diverse tasks of soluble olfactory proteins in insects","volume":"93","author":"Pelosi","year":"2018","journal-title":"Biol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00253-013-5383-y","article-title":"Structure and biotechnological applications of odorant-binding proteins","volume":"98","author":"Pelosi","year":"2014","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Raval, N., Maheshwari, R., Kalyane, D., Youngren-Ortiz, S.R., Chougule, M.B., and Tekade, R.K. (2019). Importance of physicochemical characterization of nanoparticles in pharmaceutical product development. Advances in Pharmaceutical Product Development and Research: Basic Fundamentals of Drug Delivery, Academic Press. Chapter 10.","DOI":"10.1016\/B978-0-12-817909-3.00010-8"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chemphyslip.2011.12.007","article-title":"Aqueous dispersions of DMPG in low salt contain leaky vesicles","volume":"165","author":"Barroso","year":"2012","journal-title":"Chem. Phys. Lipids"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Danaei, M., Dehghankhold, M., Ataei, S., Davarani, F.H., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, M.R. (2018). Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijpharm.2005.10.044","article-title":"On the use of the Weibull function for the discernment of drug release mechanisms","volume":"309","author":"Papadopoulou","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"493","DOI":"10.4155\/fmc-2019-0342","article-title":"New chalcone-type compounds and 2-pyrazoline derivatives: Synthesis and caspase-dependent anticancer activity","volume":"12","author":"Chouiter","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Amorim, C., Veloso, S.R.S., Castanheira, E.M.S., Hilliou, L., Pereira, R.B., Pereira, D.M., Martins, J.\u00c1., Jervis, P.J., and Ferreira, P.M.T. (2021). Bolaamphiphilic bis-dehydropeptide hydrogels as potential drug release systems. Gels, 7.","DOI":"10.26434\/chemrxiv.14261903"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and Autodock\/Vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An open-source program for chemistry aware data visualization and analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comp. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2016). Gaussian 09, RevisionD.02, Gaussian Inc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","article-title":"Automatic atom type and bond type perception in molecular mechanical calculations","volume":"25","author":"Wang","year":"2006","journal-title":"J. Mol. Graph. Mode."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lapaillerie, D., Charlier, C., Fernandes, H.S., Sousa, S.F., Lesbats, P., Weigel, P., Favereaux, A., Guyonnet-Duperat, V., and Parissi, V. (2021). In silico, in vitro and in cellulo models for monitoring SARS-CoV-2 Spike\/Human ACE2 complex, viral entry and cell fusion. Viruses, 3.","DOI":"10.1101\/2021.02.03.429555"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Martins, F.G., Melo, A., and Sousa, S.F. (2021). Identification of new potential inhibitors of quorum sensing through a specialized multi-level computational approach. Molecules, 26.","DOI":"10.3390\/molecules26092600"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.3109\/14756366.2016.1144593","article-title":"Molecular dynamic simulations and structure-based pharmacophore development for farnesyltransferase inhibitors discovery","volume":"31","author":"Moorthy","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/qua.24689","article-title":"Enzymatic \u201ctricks\u201d: Carboxylate shift and sulfur shift","volume":"114","author":"Sousa","year":"2014","journal-title":"Int. J. Quantum Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s00894-012-1590-1","article-title":"Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif","volume":"19","author":"Sousa","year":"2013","journal-title":"J. Mol. Model."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"13644","DOI":"10.1021\/jp3079748","article-title":"Chemically modified tetracyclines as inhibitors of MMP-2 matrix metalloproteinase: A molecular and structural study","volume":"116","author":"Marcial","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1016\/j.bmc.2009.03.055","article-title":"Molecular dynamics simulations on the critical states of the farnesyltransferase enzyme","volume":"17","author":"Sousa","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8681","DOI":"10.1021\/jp711214j","article-title":"Enzyme flexibility and the catalytic mechanism of farnesyltransferase: Targeting the relation","volume":"112","author":"Sousa","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-point binding free energy calculation with MM\/PBSA and MM\/GBSA: Strategies and applications in drug design","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3109\/08982100903347923","article-title":"Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation","volume":"20","author":"Diab","year":"2010","journal-title":"J. Liposome Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/21\/6616\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:24:06Z","timestamp":1760167446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/21\/6616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,31]]},"references-count":58,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["molecules26216616"],"URL":"https:\/\/doi.org\/10.3390\/molecules26216616","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,10,31]]}}}