{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:16:27Z","timestamp":1782497787925,"version":"3.54.5"},"reference-count":58,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2019,6,26]],"date-time":"2019-06-26T00:00:00Z","timestamp":1561507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 \u00b5M in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases.<\/jats:p>","DOI":"10.3390\/molecules24132348","type":"journal-article","created":{"date-parts":[[2019,6,26]],"date-time":"2019-06-26T07:24:17Z","timestamp":1561533857000},"page":"2348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-N-Oxide Derivatives"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0865-8507","authenticated-orcid":false,"given":"Florencia","family":"Ferraro","sequence":"first","affiliation":[{"name":"Laboratorio de I + D de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"},{"name":"Laboratorio de Qu\u00edmica Te\u00f3rica y Computacional, Instituto de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias, Universidad de la Rep\u00fablica, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Merlino","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Te\u00f3rica y Computacional, Instituto de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias, Universidad de la Rep\u00fablica, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Gil","sequence":"additional","affiliation":[{"name":"Laboratorio de Reproducci\u00f3n Animal, Producci\u00f3n y Reproducci\u00f3n de Rumiantes, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte-Facultad de Veterinaria, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1256-3786","authenticated-orcid":false,"given":"Hugo","family":"Cerecetto","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal, Laboratorio de Qu\u00edmica Org\u00e1nica &amp; \u00c1rea de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Rep\u00fablica, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Corvo","sequence":"additional","affiliation":[{"name":"Laboratorio de I + D de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1709-0474","authenticated-orcid":false,"given":"Mauricio","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Laboratorio de I + D de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,26]]},"reference":[{"key":"ref_1","unstructured":"Dalton, J. (1999). Fasciola gigantica: Epidemiology, control, immunology and molecular biology. Fasciolosis, CAB International."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1017\/S0031182018000914","article-title":"Human fascioliasis infection sources, their diversity, incidence factors, analytical methods and prevention measures","volume":"145","author":"Bargues","year":"2018","journal-title":"Parasitology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1097\/QCO.0000000000000482","article-title":"Recent developments in the epidemiology, diagnosis, and treatment of Fasciola infection","volume":"5","author":"Webb","year":"2018","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1017\/S0022149X16000560","article-title":"Fasciolosis in South America: Epidemiology and control challenges","volume":"2","author":"Carmona","year":"2017","journal-title":"J. Helminthol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.pt.2016.03.002","article-title":"Current Threat of Triclabendazole Resistance in Fasciola hepatica","volume":"32","author":"Kelley","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.pt.2018.05.005","article-title":"Strategies to Optimize the Efficacy of Anthelmintic Drugs in Ruminants","volume":"34","author":"Lanusse","year":"2018","journal-title":"Trends Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.vetpar.2015.01.004","article-title":"Fasciola hepatica vaccine: We may not be there yet but we\u2019re on the right road","volume":"208","author":"Mulcahy","year":"2015","journal-title":"Vet. Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/S0020-7519(03)00171-1","article-title":"Fasciola hepatica cathepsin L-like proteases: Biology, function, and potential in the development of first generation liver fluke vaccines","volume":"33","author":"Dalton","year":"2003","journal-title":"Int. J. Parasitol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.biochi.2008.04.020","article-title":"A distinctive repertoire of cathepsins is expressed by juvenile invasive Fasciola Hepatica","volume":"10","author":"Cancela","year":"2008","journal-title":"Biochimie"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cancela, M., Ru\u00e9talo, N., Dell\u2019Oca, N., da Silva, E., Smircich, P., and Rinaldi, G. (2010). Survey of transcripts expressed by the invasive juvenile stage of the liver fluke Fasciola hepatica. BMC Genomics, 11.","DOI":"10.1186\/1471-2164-11-227"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1074\/mcp.M700560-MCP200","article-title":"Proteomics and phylogenetic analysis of the cathespin L protease family of the helmith pathogen Fasciola hepatica: Expansion of a repertoire of virulence associated factors","volume":"6","author":"Robinson","year":"2008","journal-title":"Mol. Cell. Prot."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.molbiopara.2009.04.005","article-title":"The major cathepsin L secreted by the invasive juvenile Fasciola hepatica prefers proline in the S2 subsite and can cleave collagen","volume":"167","author":"Corvo","year":"2009","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1074\/mcp.RA117.000445","article-title":"Infection by the Helminth Parasite Fasciola hepatica Requires Rapid Regulation of Metabolic, Virulence, and Invasive Factors to Adjust to Its Mammalian Host","volume":"17","author":"Cwiklinski","year":"2018","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lowther, J., Robinson, M.W., Donnelly, S.M., Xu, W., Stack, C.M., Matthews, J.M., and Dalton, J.P. (2009). The importance of pH in regulating the function of the Fasciola hepatica cathepsin L1 cysteine protease. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000369"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.micinf.2011.11.012","article-title":"Fasciola hepatica virulence-associated cysteine peptidases: A systems biology perspective","volume":"14","author":"McVeigh","year":"2012","journal-title":"Microbes Infect."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ferraro, F., Merlino, A., Dell\u00b4oca, N., Gil, J., Tort, J.F., Gonzalez, M., Cerecetto, H., Cabrera, M., and Corvo, I. (2016). Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004834"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-\u00c1lvarez, L., Naranjo Feliciano, D., Hern\u00e1ndez Gonz\u00e1lez, J.E., Soares, R.O., Barreto Gomes, D.E., and Pascutti, P.G. (2015). Insights into the interactions of Fasciola hepatica cathepsin L3 with a substrate and potential novel inhibitors through in silico approaches. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003759"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Abdulla, M.H., Lim, K.C., Sajid, M., McKerrow, J.H., and Caffrey, C.R. (2007). Schistosomiasis mansoni: Novel Chemotherapy Using a Cysteine Protease Inhibitor. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040014"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vermeire, J.J., Lantz, L.D., and Caffrey, C.R. (2012). Cure of Hookworm Infection with a Cysteine Protease Inhibitor. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001680"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1084\/jem.188.4.725","article-title":"Cysteine Protease Inhibitors Cure an Experimental Trypanosoma cruzi Infection","volume":"188","author":"Engel","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.ijpara.2012.03.009","article-title":"Trypanosoma brucei: Chemical evidence that cathepsin L is essential for survival and a relevant drug target","volume":"42","author":"Steverding","year":"2012","journal-title":"Int. J. Parasitol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.1073\/pnas.0307720101","article-title":"Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum","volume":"101","author":"Sijwali","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8840","DOI":"10.1073\/pnas.0601876103","article-title":"Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems","volume":"103","author":"Liu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1080\/13543776.2017.1272572","article-title":"Cathepsin B and L inhibitors: A patent review (2010 present)","volume":"27","author":"Li","year":"2017","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ejmech.2014.06.058","article-title":"Quinoxaline, its derivatives and applications: A State of the Art review","volume":"97","author":"Pereira","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ross, F., Hern\u00e1ndez, P., Porcal, W., L\u00f3pez, G.V., Cerecetto, H., Gonz\u00e1lez, M., Basika, T., Carmona, C., Fl\u00f3, M., and Maggioli, G. (2012). Identification of thioredoxin glutathione reductase inhibitors that kill cestode and trematode parasites. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035033"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/molecules13010069","article-title":"Synthesis and Antiplasmodial Activity of 3-Furyl and 3-Thienylquinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives","volume":"13","author":"Vicente","year":"2008","journal-title":"Molecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.2174\/1381612824666180417122625","article-title":"Heterocyclic N-oxides-A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases","volume":"24","author":"Pavan","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1007\/s00436-018-5834-6","article-title":"Apoptotic impact on Brugia malayi by sulphonamido-quinoxaline: Search for a novel therapeutic rationale","volume":"117","author":"Bhoj","year":"2018","journal-title":"Parasitol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ijpara.2007.10.007","article-title":"The silencing of cysteine proteases in Fasciola hepatica newly excysted juveniles using RNA interference reduces gut penetration","volume":"38","author":"Mcgonigle","year":"2008","journal-title":"Int. J. Parasitol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1016\/j.biocel.2009.02.003","article-title":"A major cathepsin B protease from the liver fluke Fasciola hepatica has atypical active site features and a potential role in the digestive tract of newly excysted juvenile parasites","volume":"41","author":"Beckham","year":"2009","journal-title":"Int. J. Biochem. Cell Boil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/pim.12037","article-title":"Automated imaging and other developments in whole-organism anthelmintic screening","volume":"35","author":"Paveley","year":"2013","journal-title":"Parasit. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1110\/ps.9.12.2567","article-title":"A single amino acid substitution affects substrate specificity in cysteine proteinases from Fasciola hepatica","volume":"9","author":"Smooker","year":"2000","journal-title":"Protein Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fmolb.2018.00040","article-title":"Substrate Specificity of Cysteine Proteases Beyond the S2 Pocket: Mutagenesis and Molecular Dynamics Investigation of Fasciola hepatica Cathepsins L.","volume":"5","author":"Corvo","year":"2018","journal-title":"Front. Mol. Biosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1021\/acsmedchemlett.8b00397","article-title":"Prediction of Drug\u2013Target Binding Kinetics by Comparative Binding Energy Analysis","volume":"9","author":"Ganotra","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1515\/bchm.1998.379.2.137","article-title":"Revised definition of substrate binding sites of papain-like cysteine proteases","volume":"379","author":"Turk","year":"1998","journal-title":"Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13633","DOI":"10.1021\/ja074222+","article-title":"Molecular Dynamics Simulations of the Catalytic Pathway of a Cysteine Protease: A Combined QM\/MM Study of Human Cathepsin K","volume":"129","author":"Ma","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Novinec, M. (2017). Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182387"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1110\/ps.062666607","article-title":"The S2 subsites of cathepsins K and L and their contribution to collagen degradation","volume":"16","author":"Lecaille","year":"2007","journal-title":"Protein Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0166-6851(93)90172-T","article-title":"Cathepsin L proteinase secreted by Fasciola hepatica in vitro prevents antibody-mediated eosinophil attachment to newly excysted juveniles","volume":"62","author":"Carmona","year":"1993","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"179","DOI":"10.2307\/3280632","article-title":"Cultivation of Schistosoma In Vitro. I. Establishment of culture from cercariae and development until pairing","volume":"67","author":"Basch","year":"1981","journal-title":"J. Parasitol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Robinson, M.W., Corvo, I., Jones, P.M., George, A.M., Padula, M.P., To, J., Cancela, M., Rinaldi, G., Tort, J.F., and Roche, L. (2011). Collagenolytic Activities of the Major Secreted Cathepsin L Peptidases Involved in the Virulence of the Helminth Pathogen, Fasciola hepatica. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001012"},{"key":"ref_43","unstructured":"Case, D.A., Cerutti, D.S., Cheatham, T.E., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., Goetz, A.W., Greene, D., and Homeyer, N. (2017). AMBER 16, University of California."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1002\/jcc.10349","article-title":"A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations","volume":"24","author":"Duan","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1080\/00268978800101881","article-title":"An analysis of the accuracy of Langevin and molecular dynamics algorithms","volume":"65","author":"Pastor","year":"1988","journal-title":"Mol. Phys."},{"key":"ref_49","first-page":"327","article-title":"Numerical-integration of cartesian equations of motion of a system with constraints-molecular-dynamics of N-alkanes","volume":"23","author":"Ryekaert","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1021\/ct700119m","article-title":"Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms","volume":"3","author":"Shao","year":"2007","journal-title":"J. Chem. Theory Comput."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD-Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_52","first-page":"6615","article-title":"Long-range corrected hybrid density fuctionals with dumped atom-atom dispersion corrections","volume":"10","author":"Chai","year":"2008","journal-title":"J. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1063\/1.438955","article-title":"Self-Consistent Molecular Orbital Methods. XX. A Basis set for correlated wave-functions","volume":"72","author":"Krishnan","year":"1980","journal-title":"J. Chem. Phys."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1063\/1.474659","article-title":"A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropics dielectrics","volume":"107","author":"Cances","year":"1997","journal-title":"J. Chem. Phys."},{"key":"ref_55","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H.X. (2009). Gaussian 09, Gaussian Inc.. Revision A.02."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_57","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. Comput. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/jcc.540110311","article-title":"Determining atom-centered monopoles from molecular electrostatics potentials\u2013The need for high sampling density in formamide conformational analysis","volume":"11","author":"Breneman","year":"1990","journal-title":"J. Comput. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/13\/2348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:01:14Z","timestamp":1760187674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/13\/2348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,26]]},"references-count":58,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["molecules24132348"],"URL":"https:\/\/doi.org\/10.3390\/molecules24132348","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,26]]}}}