{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:33:17Z","timestamp":1760149997593,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T00:00:00Z","timestamp":1696550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 \u00b5g\/kg and 55 \u00b5g\/kg, respectively. A notable finding was RetroABZ\u2019s significantly improved water solubility (245.74 \u00b5g\/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the \u03b2-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the \u03b2-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ\u2019s potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.<\/jats:p>","DOI":"10.3390\/ijms241914949","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T07:49:29Z","timestamp":1696578569000},"page":"14949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Enhancing Giardicidal Activity and Aqueous Solubility through the Development of \u201cRetroABZ\u201d, a Regioisomer of Albendazole: In Vitro, In Vivo, and In Silico Studies"],"prefix":"10.3390","volume":"24","author":[{"given":"Carlos","family":"Mart\u00ednez-Conde","sequence":"first","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"Col\u00edn-Lozano","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abraham","family":"Guti\u00e9rrez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuel","family":"Hern\u00e1ndez-N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Departamento de Recursos del Mar, Centro de Investigaci\u00f3n y de Estudios Avanzados, IPN, Unidad M\u00e9rida, Merida 97310, Yucat\u00e1n, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-5671","authenticated-orcid":false,"given":"Lili\u00e1n","family":"Y\u00e9pez-Mulia","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Medica en Enfermedades Infecciosas y Parasitarias, Unidad M\u00e9dica de Alta Especialidad-Hospital de Pediatr\u00eda, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Fernando","family":"Colorado-Pablo","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-5397","authenticated-orcid":false,"given":"Rodrigo","family":"Aguayo-Ortiz","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-0244","authenticated-orcid":false,"given":"Jaime","family":"Escalante","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Qu\u00edmicas-IICBA, Universidad Aut\u00f3noma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-1791","authenticated-orcid":false,"given":"Julio C.","family":"Rivera-Leyva","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica Nayelli","family":"S\u00e1nchez-Carranza","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7111-7922","authenticated-orcid":false,"given":"Elizabeth","family":"Barbosa-Cabrera","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, IPN, Mexico City 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5344-4762","authenticated-orcid":false,"given":"Gabriel","family":"Navarrete-Vazquez","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.apar.2021.08.007","article-title":"Towards global control of parasitic diseases in the Covid-19 era: One Health and the future of multisectoral global health governance","volume":"114","author":"Ung","year":"2021","journal-title":"Adv. Parasitol."},{"key":"ref_2","first-page":"1178633617732296","article-title":"Climate Change Contribution to the Emergence or Re-Emergence of Parasitic Diseases","volume":"10","author":"Short","year":"2017","journal-title":"Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40249-020-0630-9","article-title":"Neglected tropical diseases: An effective global response to local poverty-related disease priorities","volume":"9","author":"Engels","year":"2020","journal-title":"Infect. Dis. Poverty"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.pt.2006.02.015","article-title":"Giardia and Cryptosporidium join the \u201cNeglected Diseases Initiative\u201d","volume":"22","author":"Savioli","year":"2006","journal-title":"Trends Parasitol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1038\/s41467-023-38363-2","article-title":"Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy","volume":"14","author":"Giallourou","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/s40475-021-00248-z","article-title":"Giardia duodenalis Virulence \u201cTo Be, or Not To Be\u201d","volume":"8","year":"2021","journal-title":"Curr. Trop. Med. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpara.2018.07.003","article-title":"Giardia: An under-reported foodborne parasite","volume":"49","author":"Ryan","year":"2019","journal-title":"Int. J. Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ijpddr.2022.05.004","article-title":"3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity","volume":"19","author":"Zheng","year":"2022","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2174\/1573406412666160811112408","article-title":"Synthesis, Screening and in silico Simulations of Anti-Parasitic Propamidine\/Benzimidazole Derivatives","volume":"13","author":"Tlahuext","year":"2017","journal-title":"Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.biotechadv.2015.04.009","article-title":"Drug resistance in Giardia duodenalis","volume":"33","author":"Ansell","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/bs.apar.2019.11.003","article-title":"Drug resistance in Giardia: Mechanisms and alternative treatments for Giardiasis","volume":"107","author":"Leitsch","year":"2020","journal-title":"Adv. Parasitol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-N\u00fa\u00f1ez, E., Tlahuext, H., Moo-Puc, R., Moreno, D., Gonz\u00e1lez-D\u00edaz, M.O., and Navarrete-V\u00e1zquez, G. (2017). Design, synthesis and biological evaluation of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-narylacetamides as antiprotozoal agents. Molecules, 22.","DOI":"10.3390\/molecules22040579"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-Ochoa, B., Mart\u00ednez-Rosas, V., Morales-Luna, L., Calder\u00f3n-Jaimes, E., Rocha-Ram\u00edrez, L.M., Ortega-Cuellar, D., Rufino-Gonz\u00e1lez, Y., Gonz\u00e1lez-Valdez, A., Arreguin-Espinosa, R., and Enr\u00edquez-Flores, S. (2022). Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis. Molecules, 27.","DOI":"10.3390\/molecules27248902"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.ijpddr.2021.05.003","article-title":"In vitro selection of Giardia duodenalis for Albendazole resistance identifies a \u03b2-tubulin mutation at amino acid E198K","volume":"16","author":"Su","year":"2021","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jpba.2005.03.010","article-title":"Development and optimization of a rapid HPLC method for analysis of ricobendazole and albendazole sulfone in sheep plasma","volume":"39","author":"Wu","year":"2005","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"435","DOI":"10.4103\/1735-5362.194868","article-title":"Dramatic improvement in dissolution rate of albendazole by a simple, one-step, industrially scalable technique","volume":"11","author":"Ghanbarzadeh","year":"2016","journal-title":"Res. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1021\/mp500539g","article-title":"Investigating Albendazole Desmotropes by Solid-State NMR Spectroscopy","volume":"12","author":"Chattah","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Col\u00edn-Lozano, B., Estrada-Soto, S., Ch\u00e1vez-Silva, F., Guti\u00e9rrez-Hern\u00e1ndez, A., Cer\u00f3n-Romero, L., Giacoman-Mart\u00ednez, A., Almanza-P\u00e9rez, J.C., Hern\u00e1ndez-N\u00fa\u00f1ez, E., Wang, Z., and Xie, X. (2018). Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids. Molecules, 23.","DOI":"10.20944\/preprints201801.0079.v1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rocha-Gardu\u00f1o, G., Hern\u00e1ndez-Mart\u00ednez, N.A., Col\u00edn-Lozano, B., Estrada-Soto, S., Hern\u00e1ndez-N\u00fa\u00f1ez, E., Prieto-Mart\u00ednez, F.D., Medina-Franco, J.L., Chale-Dzul, J.B., Moo-Puc, R., and Navarrete-V\u00e1zquez, G. (2020). Metronidazole and secnidazole carbamates: Synthesis, antiprotozoal activity, and molecular dynamics studies. Molecules, 25.","DOI":"10.3390\/molecules25040793"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1016\/j.bmcl.2017.05.071","article-title":"Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum","volume":"27","author":"Scior","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1021\/acsomega.1c05519","article-title":"In Silico and in Vitro Studies for Benzimidazole Anthelmintics Repurposing as VEGFR-2 Antagonists: Novel Mebendazole-Loaded Mixed Micelles with Enhanced Dissolution and Anticancer Activity","volume":"7","author":"Elmaaty","year":"2022","journal-title":"ACS Omega"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2478\/v10007-012-0031-0","article-title":"Formulation development of an albendazole self-emulsifying drug delivery system (SEDDS) with enhanced systemic exposure","volume":"62","author":"Meena","year":"2012","journal-title":"Acta Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1021\/jm101356p","article-title":"Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry","volume":"54","author":"Ishikawa","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dom\u00ednguez-Mendoza, E.A., Galv\u00e1n-Cipr\u00e9s, Y., Mart\u00ednez-Miranda, J., Miranda-Gonz\u00e1lez, C., Col\u00edn-Lozano, B., Hern\u00e1ndez-N\u00fa\u00f1ez, E., Hern\u00e1ndez-Bolio, G.I., Palomino-Hern\u00e1ndez, O., and Navarrete-Vazquez, G. (2021). Design, synthesis, and in silico multitarget pharmacological simulations of acid bioisosteres with a validated in vivo antihyperglycemic effect. Molecules, 26.","DOI":"10.3390\/molecules26040799"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"2","author":"Xiong","year":"2021","journal-title":"Nucl. Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jmgm.2013.07.008","article-title":"Molecular basis for benzimidazole resistance from a novel \u03b2-tubulin binding site model","volume":"45","author":"Castillo","year":"2013","journal-title":"J. Mol. Graph."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Eren, E., Watts, N.R., Sacett, D.L., and Wingfield, P.T. (2021). Conformational changes in tubulin upon binding cryptophycin-52 reveal its mechanism of action. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.101138"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13775","DOI":"10.1073\/pnas.0904223106","article-title":"Variations in the colchicine-binding domain provide insight into the structural switch of tubulin","volume":"106","author":"Gigant","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Buscemi, C., Randazzo, C., Buscemi, P., Caldarella, R., Lombardo, M., and Buscemi, S. (2023). Very Prolonged Treatment with Albendazole of a Case of Disseminated Abdominal Cystic Echinococcosis. Trop. Med. Infect. Dis., 8.","DOI":"10.3390\/tropicalmed8090449"},{"key":"ref_30","first-page":"CD007787","article-title":"Drugs for treating giardiasis","volume":"2","author":"Granados","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_31","first-page":"908","article-title":"Benzimidazole derivatives as inhibitors of the oxidation of polypropylene and the effect of p-hydroxydiphenylamine on their efficiency","volume":"5","author":"Lukovnikov","year":"1964","journal-title":"Polym. Sci."},{"key":"ref_32","first-page":"353","article-title":"Studies on the Selective S-oxidation of Albendazole, Fenbendazole, Triclabendazole, and Other Benzimidazole Sulfides","volume":"49","author":"Castillo","year":"2005","journal-title":"J. Mex. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1016\/S0968-0896(03)00497-8","article-title":"Synthesis and antiparasitic activity of albendazole and mebendazole analogues","volume":"11","author":"Tapia","year":"2003","journal-title":"Bioorg. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1083\/jcb.106.3.761","article-title":"Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line","volume":"106","author":"Boukamp","year":"1988","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Carranza, J.N., Alvarez, L., Marquina-Bahena, S., Salas-Vidal, E., Cuevas, V., Jim\u00e9nez, E.W., Veloz, G.R.A., Carraz, M., and Gonz\u00e1lez-Maya, L. (2017). Phenolic compounds isolated from Caesalpinia coriaria induce S and G2\/M phase cell cycle arrest differentially and trigger cell death by interfering with microtubule dynamics in cancer cell lines. Molecules, 22.","DOI":"10.3390\/molecules22040666"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.jep.2006.09.009","article-title":"In vivo antigiardial activity of three flavonoids isolated of some medicinal plants used in Mexican traditional medicine for the treatment of diarrhea","volume":"109","author":"Barbosa","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.carbpol.2011.08.009","article-title":"Diversity in the supramolecular interactions of 5,6-dichloro-2-(trifluoromethyl)-1H-benzimidazole with modified cyclodextrins: Implications for physicochemical properties and antiparasitic activity","volume":"87","author":"Castillo","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0378-4347(00)82695-X","article-title":"Sensitive high-performance liquid chromatographic assay for albendazole and its main metabolite albendazole sulphoxide in plasma and cerebrospinal fluid","volume":"494","author":"Hurtado","year":"1989","journal-title":"J. Chromatogr."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1021\/acs.jcim.9b00439","article-title":"Scalable Molecular Force Field Parameterization Method Based on Density Functional Theory and Quantum-Level Machine Learning","volume":"59","author":"Galvelis","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1493","DOI":"10.1002\/wcms.1493","article-title":"Extended tight-binding quantum chemistry methods","volume":"11","author":"Bannwarth","year":"2021","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1021\/acs.jctc.0c00121","article-title":"Extending the Applicability of the ANI Deep Learning Molecular Potential to Sulfur and Halogens","volume":"16","author":"Devereux","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sousa da Silva, A.W., and Vranken, W.F. (2012). ACPYPE\u2014AnteChamber PYthon Parser interfacE. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-367"},{"key":"ref_44","unstructured":"Wu, C.Y., and Wang, Y.X. (2022, January 05). PPA in Complex with Tubulin. Available online: https:\/\/www.wwpdb.org\/pdb?id=pdb_00007dbc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1093\/bioinformatics\/btz828","article-title":"QMEANDisCo distance constraints applied on model quality estimation","volume":"36","author":"Studer","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13321-021-00522-2","article-title":"GNINA 1.0: Molecular docking with deep learning","volume":"13","author":"McNutt","year":"2021","journal-title":"J. Cheminform."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/jcc.10262","article-title":"Development of polyphosphate parameters for use with the AMBER force field","volume":"24","author":"Meagher","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: Expanding the scope of the protein\u2013ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucl. Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5722","DOI":"10.1021\/jacs.6b02682","article-title":"Interaction Entropy: A New Paradigm for Highly Efficient and Reliable Computation of Protein\u2013Ligand Binding Free Energy","volume":"138","author":"Duan","year":"2016","journal-title":"J. Am. Chem. Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14949\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:01:56Z","timestamp":1760130116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,6]]},"references-count":54,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914949"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914949","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,10,6]]}}}