{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T06:36:51Z","timestamp":1777531011179,"version":"3.51.4"},"reference-count":128,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T00:00:00Z","timestamp":1573430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Obra Social &quot;la Caixa&quot; and Fundaci\u00f3n Caja Navarra","award":["LCF\/PR\/PR13\/11080005"],"award-info":[{"award-number":["LCF\/PR\/PR13\/11080005"]}]},{"name":"Gobierno de Navarra Salud","award":["12\/2017"],"award-info":[{"award-number":["12\/2017"]}]},{"name":"Fundaci\u00f3n Roviralta","award":["2019"],"award-info":[{"award-number":["2019"]}]},{"name":"Fundaci\u00f3n Garcilaso de la Vega","award":["2019"],"award-info":[{"award-number":["2019"]}]},{"name":"Ubesol","award":["2019"],"award-info":[{"award-number":["2019"]}]},{"name":"Laser Ebro and Government of Navarre","award":["LEISHUM"],"award-info":[{"award-number":["LEISHUM"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser\/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.<\/jats:p>","DOI":"10.3390\/biom9110723","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Novel Serine\/Threonine Protein Kinase LmjF.22.0810 from Leishmania major May Be Involved in the Resistance to Drugs such as Paromomycin"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8784-8295","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Vacas","sequence":"first","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-8121","authenticated-orcid":false,"given":"Celia","family":"Fern\u00e1ndez-Rubio","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Algarabel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9183-6369","authenticated-orcid":false,"given":"Jos\u00e9","family":"Pe\u00f1a-Guerrero","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1443-6513","authenticated-orcid":false,"given":"Esther","family":"Larrea","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Rocha Formiga","sequence":"additional","affiliation":[{"name":"Aggeu Magalh\u00e3es Institute, Oswaldo Cruz Foundation (FIOCRUZ). Graduate Program in Applied Cellular and Molecular Biology (BCMA), University of Pernambuco (UPE), Recife\/PE 50.670-420, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0542-4446","authenticated-orcid":false,"given":"Alfonso T.","family":"Garc\u00eda-Sosa","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Ravila 14a, 54011 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-7316","authenticated-orcid":false,"given":"Paul A.","family":"Nguewa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, E-31008 Navarra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2147\/TCRM.S30139","article-title":"Interest in paromomycin for the treatment of visceral leishmaniasis (Kala-azar)","volume":"8","author":"Wiwanitkit","year":"2012","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1074-5521(99)80016-7","article-title":"Aminoglycoside antibiotic phosphotransferases are also serine protein kinases","volume":"6","author":"Daigle","year":"1999","journal-title":"Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.drup.2010.08.003","article-title":"Aminoglycoside modifying enzymes","volume":"13","author":"Ramirez","year":"2010","journal-title":"Drug Resist. Updates"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"42786","DOI":"10.1074\/jbc.A110.194266","article-title":"Structure and function of APH(4)-Ia, a hygromycin B resistance enzyme","volume":"286","author":"Stogios","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1365-3156.2001.00778.x","article-title":"Drug resistance in Indian visceral leishmaniasis","volume":"6","author":"Sundar","year":"2001","journal-title":"Trop. Med. Int. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16092","DOI":"10.1038\/nmicrobiol.2016.92","article-title":"Drug resistance in eukaryotic microorganisms","volume":"1","author":"Fairlamb","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_7","first-page":"149","article-title":"Drug resistance in","volume":"19","author":"Chemother","year":"2000","journal-title":"Commun. Dis. Rep. Cdr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1093\/emboj\/21.8.1881","article-title":"Life without transcriptional control? From fly to man and back again","volume":"21","author":"Clayton","year":"2002","journal-title":"EMBO J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1093\/emboj\/17.9.2619","article-title":"A mitogen-activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host","volume":"17","author":"Wiese","year":"1998","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1074\/mcp.M800556-MCP200","article-title":"The phosphoproteome of bloodstream form Trypanosoma brucei, causative agent of African sleeping sickness","volume":"8","author":"Nett","year":"2009","journal-title":"Mol. Cell. Proteom."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1002\/pmic.200800874","article-title":"Phosphoproteomic analysis of the human pathogen Trypanosoma cruzi at the epimastigote stage","volume":"9","author":"Nakayasu","year":"2009","journal-title":"Proteomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1074\/mcp.M114.040329","article-title":"Quantitative proteomic and phosphoproteomic analysis of Trypanosoma cruzi amastigogenesis","volume":"13","author":"Queiroz","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1021\/pr4002492","article-title":"Phosphoproteomic analysis of differentiating Leishmania parasites reveals a unique stage-specific phosphorylation motif","volume":"12","author":"Tsigankov","year":"2013","journal-title":"J. Proteome Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.drudis.2015.07.008","article-title":"Small-molecule kinase inhibitors: An analysis of FDA-approved drugs","volume":"21","author":"Wu","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/pros.22980","article-title":"Sunitinib reduces tumor hypoxia and angiogenesis, and radiosensitizes prostate cancer stem-like cells","volume":"75","author":"Diaz","year":"2015","journal-title":"Prostate"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.2174\/092986712800672076","article-title":"The Quinoline Imidoselenocarbamate EI201 Blocks the AKT\/mTOR Pathway and Targets Cancer Stem Cells Leading to a Strong Antitumor Activity","volume":"19","author":"Ibanez","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1517\/13543784.2011.541153","article-title":"Tyrosine kinase inhibitors with antiangiogenic properties for the treatment of non-small cell lung cancer","volume":"20","author":"Nguewa","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1021\/cb5008376","article-title":"Small molecule substrate phosphorylation site inhibitors of protein kinases: Approaches and challenges","volume":"10","author":"Breen","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Crowther, G.J., Shanmugam, D., Carmona, S.J., Doyle, M.A., Hertz-Fowler, C., Berriman, M., Nwaka, S., Ralph, S.A., Roos, D.S., and van Voorhis, W.C. (2010). Identification of attractive drug targets in neglected- disease pathogens using an in Silico approach. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000804"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.bbapap.2005.08.018","article-title":"Protein kinases as drug targets in trypanosomes and Leishmania","volume":"1754","author":"Naula","year":"2005","journal-title":"Biochim. Biophys. Acta-Proteins Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11280","DOI":"10.1021\/cr500197d","article-title":"Kinases as druggable targets in trypanosomatid protozoan parasites","volume":"114","author":"Merritt","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Parsons, M., Worthey, E.A., Ward, P.N., and Mottram, J.C. (2005). Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genom., 6.","DOI":"10.1186\/1471-2164-6-127"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/j.bmcl.2016.03.103","article-title":"Repurposing strategies for tropical disease drug discovery","volume":"26","author":"Klug","year":"2016","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7921","DOI":"10.1021\/jm8010299","article-title":"Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states","volume":"51","author":"Kufareva","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7731","DOI":"10.1021\/jm800758s","article-title":"Search for inhibitors of bacterial and human protein kinases among derivatives of diazepines[1,4] annelated with maleimide and indole cycles","volume":"51","author":"Danilenko","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Diaz, R., Nguewa, P.A., Parrondo, R., Perez-Stable, C., Manrique, I., Redrado, M., Catena, R., Collantes, M., Pe\u00f1uelas, I., and D\u00edaz-Gonz\u00e1lez, J.A. (2010). Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-188"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/sj.bjc.6604938","article-title":"The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer","volume":"100","author":"Diaz","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fl\u00f3rez, A.F., Park, D., Bhak, J., Kim, B.C., Kuchinsky, A., Morris, J.H., Espinosa, J., and Muskus, C. (2010). Protein network prediction and topological analysis in Leishmania major as a tool for drug target selection. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-484"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1021\/cb300663j","article-title":"Strategies for the selective regulation of kinases with allosteric modulators: Exploiting exclusive structural features","volume":"8","author":"Fang","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.phrs.2015.10.021","article-title":"Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes","volume":"103","author":"Roskoski","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/nchembio.1938","article-title":"The ins and outs of selective kinase inhibitor development","volume":"11","author":"Chaikuad","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.2174\/138161212800672813","article-title":"New Directions in Targeting Protein Kinases: Focusing Upon True Allosteric and Bivalent Inhibitors","volume":"18","author":"Lamba","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ceca.2014.10.015","article-title":"Calcium signaling in trypanosomatid parasites","volume":"57","author":"Docampo","year":"2015","journal-title":"Cell Calcium"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkp851","article-title":"TriTrypDB: A functional genomic resource for the Trypanosomatidae","volume":"38","author":"Aslett","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: Multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/bioinformatics\/bts199","article-title":"Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data","volume":"28","author":"Kearse","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0168-9525(00)02024-2","article-title":"EMBOSS: The European Molecular Biology Open Software Suite","volume":"16","author":"Rice","year":"2000","journal-title":"Trends Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D205","DOI":"10.1093\/nar\/gkn845","article-title":"CDD: Specific functional annotation with the Conserved Domain Database","volume":"37","author":"Anderson","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D225","DOI":"10.1093\/nar\/gkq1189","article-title":"CDD: A Conserved Domain Database for the functional annotation of proteins","volume":"39","author":"Lu","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"W337","DOI":"10.1093\/nar\/gku366","article-title":"PredictProtein\u2014An open resource for online prediction of protein structural and functional features","volume":"42","author":"Yachdav","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D190","DOI":"10.1093\/nar\/gkw1107","article-title":"InterPro in 2017-beyond protein family and domain annotations","volume":"45","author":"Finn","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D279","DOI":"10.1093\/nar\/gkv1344","article-title":"The Pfam protein families database: Towards a more sustainable future","volume":"44","author":"Finn","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/prot.21139","article-title":"Prediction of EF-hand calcium-binding proteins and analysis of bacterial EF-hand proteins","volume":"65","author":"Zhou","year":"2006","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pierleoni, A., Martelli, P.L., and Casadio, R. (2008). PredGPI: A GPI-anchor predictor. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-392"},{"key":"ref_45","first-page":"531","article-title":"Protein identification and analysis tools in the ExPASy server","volume":"112","author":"Wilkins","year":"1999","journal-title":"Methods Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1006\/jmbi.1999.3310","article-title":"Sequence and structure-based prediction of eukaryotic protein phosphorylation sites","volume":"294","author":"Blom","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nmeth.1701","article-title":"SignalP 4.0: Discriminating signal peptides from transmembrane regions","volume":"8","author":"Petersen","year":"2011","journal-title":"Nat. Methods"},{"key":"ref_48","unstructured":"Harrington, B., and Engelen, J. (2009, October 20). Inkscape. Available online: http:\/\/www.inkscape.Org."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1093\/nar\/gkf436","article-title":"MAFFT: A novel method for rapid multiple sequence alignment based on fast Fourier transform","volume":"30","author":"Katoh","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1093\/bioinformatics\/bti263","article-title":"ProtTest: Selection of best-fit models of protein evolution","volume":"21","author":"Abascal","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1093\/molbev\/msn067","article-title":"An improved general amino acid replacement matrix","volume":"25","author":"Le","year":"2008","journal-title":"Mol. Biol. Evol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3497","DOI":"10.1093\/nar\/gkg500","article-title":"Multiple sequence alignment with the Clustal series of programs","volume":"31","author":"Chenna","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"W526","DOI":"10.1093\/nar\/gkh468","article-title":"Protein structure prediction and analysis using the Robetta server","volume":"32","author":"Kim","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1107\/S0907444902003451","article-title":"The protein data bank","volume":"58","author":"Berman","year":"2002","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_56","first-page":"E4532","article-title":"Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress","volume":"111","author":"Moreno","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"085201","DOI":"10.1088\/1751-8113\/44\/8\/085201","article-title":"A \u201cmissing\u201d family of classical orthogonal polynomials","volume":"44","author":"Vinet","year":"2011","journal-title":"J. Phys. A Math. Theor."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/prot.22570","article-title":"Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8","volume":"77","author":"Krieger","year":"2009","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0076-6879(97)77022-8","article-title":"VERIFY3D: Assessment of protein models with three-dimensional profiles","volume":"277","author":"Eisenberg","year":"1997","journal-title":"Methods Enzymol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/bioinformatics\/btq662","article-title":"Toward the estimation of the absolute quality of individual protein structure models","volume":"27","author":"Benkert","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"W510","DOI":"10.1093\/nar\/gkp322","article-title":"QMEAN server for protein model quality estimation","volume":"37","author":"Benkert","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/prot.21715","article-title":"QMEAN: A comprehensive scoring function for model quality assessment","volume":"71","author":"Benkert","year":"2008","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Benkert, P., Schwede, T., and Tosatto, S.C. (2009). QMEANclust: Estimation of protein model quality by combining a composite scoring function with structural density information. BMC Struct. Biol., 9.","DOI":"10.1186\/1472-6807-9-35"},{"key":"ref_64","first-page":"187","article-title":"ANOLEA: A www server to assess protein structures","volume":"5","author":"Melo","year":"1997","journal-title":"Proc. Int. Conf. Intell. Syst. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/1471-2105-7-324","article-title":"Novel knowledge-based mean force potential at the profile level","volume":"7","author":"Dong","year":"2006","journal-title":"BMC Bioinform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1006\/jmbi.1998.1665","article-title":"Assessing protein structures with a non-local atomic interaction energy","volume":"277","author":"Melo","year":"1998","journal-title":"J. Mol. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program to check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_68","unstructured":"van Gunsteren, W.F., Billeter, S.R., Eising, A.A., H\u00fcnenberger, P.H., Kr\u00fcger, P., Mark, A.E., Scott, W.R.P., and Tironi, I.G. (1996). Biomolecular Simulation: The {GROMOS96} Manual and User Guide, Vdf Hochschulverlag AG an der ETH Z\u00fcrich."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: Pattern recognition of hydrogen--bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/pro.5560050204","article-title":"PROMOTIF-A program to identify and analyze structural motifs in proteins","volume":"5","author":"Hutchinson","year":"2008","journal-title":"Protein Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/prot.340170404","article-title":"Recognition of errors in three--dimensional structures of proteins","volume":"17","author":"Sippl","year":"1993","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1002\/pro.5560020916","article-title":"Verification of protein structures: Patterns of nonbonded atomic interactions","volume":"2","author":"Colovos","year":"1993","journal-title":"Protein Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6474","DOI":"10.1021\/jp003919d","article-title":"Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides","volume":"105","author":"Kaminski","year":"2001","journal-title":"J. Phys. Chem. B"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., and Hermans, J. (1981). Interaction Models for Water in Relation to Protein Hydration. Intermolecular Forces, Springer, Dordrecht.","DOI":"10.1007\/978-94-015-7658-1_21"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14101","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_77","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_78","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_79","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_80","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Adzhigirey","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Rostkowski, M., Olsson, M.H., S\u00f8ndergaard, C.R., and Jensen, J.H. (2011). Graphical analysis of pH-dependent properties of proteins predicted using PROPKA. BMC Struct. Biol., 11.","DOI":"10.1186\/1472-6807-11-6"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/j.1747-0285.2007.00483.x","article-title":"New method for fast and accurate binding-site identification and analysis","volume":"69","author":"Halgren","year":"2007","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1021\/ci800324m","article-title":"Identifying and characterizing binding sites and assessing druggability","volume":"49","author":"Halgren","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC\u2014A free database of commercially available compounds for virtual screening","volume":"45","author":"Irwin","year":"2005","journal-title":"J. Chem. Inf. Model."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: A software program for pKa prediction and protonation state generation for drug-like molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s10822-010-9349-1","article-title":"Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution","volume":"24","author":"Greenwood","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1964531","DOI":"10.1155\/2017\/1964531","article-title":"Construction of Two mCherry Plasmids (pXG-mCherry) for Transgenic Leishmania: Valuable Tools for Future Molecular Analysis","volume":"2017","author":"Vacas","year":"2017","journal-title":"J. Parasitol. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0166-6851(93)90231-L","article-title":"Rapid isolation of DNA from trypanosomatid protozoa using a simple \u201cmini-prep\u201d procedure","volume":"59","author":"Cross","year":"1993","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7170","DOI":"10.1073\/pnas.88.16.7170","article-title":"Double targeted gene replacement for creating null mutants","volume":"88","author":"Cruz","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"564","DOI":"10.4049\/jimmunol.135.1.564","article-title":"Identification of cell surface carbohydrate and antigenic changes between noninfective and infective developmental stages of Leishmania major promastigotes","volume":"135","author":"Sacks","year":"1985","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5705","DOI":"10.1128\/AAC.00997-15","article-title":"Leishmanicidal activities of novel methylseleno-imidocarbamates","volume":"59","author":"Campbell","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_94","unstructured":"Dame, N. (2015). GraphPad Prism, Version 7.0, Software for Technical Computation, GraphPad Software, Inc."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Wang, J., Pan, C., Wang, Y., Ye, L., Wu, J., Chen, L., Zou, T., and Lu, G. (2015). Genome-wide identification of MAPK, MAPKK, and MAPKKK gene families and transcriptional profiling analysis during development and stress response in cucumber. BMC Genomics, 16.","DOI":"10.1186\/s12864-015-1621-2"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.molcel.2004.08.024","article-title":"Regulation of protein kinases: Controlling activity through activation segment conformation","volume":"15","author":"Nolen","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0065-3233(00)54003-0","article-title":"Amino acid substitution matrices","volume":"54","author":"Henikoff","year":"2000","journal-title":"Adv. Protein Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"19643","DOI":"10.1074\/jbc.A112.411934","article-title":"Erratum: Characterization of plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) and its role in microneme secretion during erythrocyte invasion","volume":"288","author":"Bansal","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"10115","DOI":"10.1038\/srep10115","article-title":"Functional role of histidine in the conserved His-x-Asp motif in the catalytic core of protein kinases","volume":"5","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1098\/rstb.2012.0054","article-title":"Evolution of the eukaryotic protein kinases as dynamic molecular switches","volume":"367","author":"Taylor","year":"2012","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/cr.2009.6","article-title":"DOG 1.0: Illustrator of protein domain structures","volume":"19","author":"Ren","year":"2009","journal-title":"Cell Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/520435","article-title":"Cystathionine \u03b2 -Lyase-Like Protein with Pyridoxal Binding Domain Characterized in Leishmania major by Comparative Sequence Analysis and Homology Modelling","volume":"2013","author":"Negi","year":"2013","journal-title":"ISRN Comput. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.tibs.2010.09.006","article-title":"Protein kinases: Evolution of dynamic regulatory proteins","volume":"36","author":"Taylor","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1111\/bph.13096","article-title":"Ten things you should know about protein kinases: IUPHAR Review 14","volume":"172","author":"Fabbro","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Xu, M., Yu, L., Wan, B., Yu, L., and Huang, Q. (2011). Predicting inactive conformations of protein kinases using active structures: Conformational selection of Type-II inhibitors. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022644"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1529\/biophysj.104.052423","article-title":"Mechanically induced titin kinase activation studied by force-probe molecular dynamics simulations","volume":"88","author":"Shen","year":"2005","journal-title":"Biophys. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2015.07.010","article-title":"A historical overview of protein kinases and their targeted small molecule inhibitors","volume":"100","author":"Roskoski","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.phrs.2015.01.003","article-title":"Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors","volume":"94","author":"Roskoski","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1073\/pnas.1207104110","article-title":"Identification of a hidden strain switch provides clues to an ancient structural mechanism in protein kinases","volume":"110","author":"Oruganty","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13333","DOI":"10.1073\/pnas.1307365110","article-title":"Identification of the molecular attributes required for aminoglycoside activity against Leishmania","volume":"110","author":"Shalev","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jmb.2004.11.073","article-title":"Mutagenesis of 16S rRNA C1409-G1491 base-pair differentiates between 6\u2032OH and 6\u2032NH3+ aminoglycosides","volume":"346","author":"Pfister","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.trstmh.2008.09.008","article-title":"Paromomycin","volume":"103","author":"Davidson","year":"2009","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1128\/AAC.26.5.745","article-title":"Development of topical treatment for cutaneous leishmaniasis caused by Leishmania major in experimental animals","volume":"26","author":"Jacobs","year":"1984","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Oruganty, K., Talevich, E.E., Neuwald, A.F., and Kannan, N. (2016). Identification and classification of small molecule kinases: Insights into substrate recognition and specificity Genome evolution and evolutionary systems biology. BMC Evol. Biol., 16.","DOI":"10.1186\/s12862-015-0576-x"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.jmb.2005.06.057","article-title":"Did protein kinase regulatory mechanisms evolve through elaboration of a simple structural component?","volume":"351","author":"Kannan","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1002\/prot.24104","article-title":"PRL-dock: Protein-ligand docking based on hydrogen bond matching and probabilistic relaxation labeling","volume":"80","author":"Wu","year":"2012","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/mr.57.1.138-163.1993","article-title":"Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes","volume":"57","author":"Shaw","year":"1993","journal-title":"Microbiol. Rev."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"7001","DOI":"10.1021\/bi0256680","article-title":"Mechanism of aminoglycoside antibiotic kinase APH(3\u2032)-IIIa: Role of the nucleotide positioning loop","volume":"41","author":"Thompson","year":"2002","journal-title":"Biochemistry"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1128\/AAC.37.1.78","article-title":"Overproduction of 3\u2032-aminoglycoside phosphotransferase type I confers resistance to tobramycin in Escherichia coli","volume":"37","author":"Menard","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1128\/AAC.47.5.1577-1583.2003","article-title":"Aminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase","volume":"47","author":"Magnet","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1006\/excr.1997.3500","article-title":"In vivo interference of paromomycin with mitochondrial activity of Leishmania","volume":"232","author":"Maarouf","year":"1997","journal-title":"Exp. Cell Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1128\/AAC.01574-13","article-title":"Elucidation of cellular mechanisms involved in experimental paromomycin resistance in leishmania donoVani","volume":"58","author":"Bhandari","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Chawla, B., Jhingran, A., Panigrahi, A., Stuart, K.D., and Madhubala, R. (2011). Paromomycin affects translation and vesicle-mediated trafficking as revealed by proteomics of paromomycin -susceptible -resistant leishmania donovani. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026660"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1128\/AAC.49.5.1988-1993.2005","article-title":"Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes","volume":"49","author":"Messier","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"10330","DOI":"10.1038\/s41598-017-09720-1","article-title":"Miltefosine Resistant Field Isolate from Indian Kala-Azar Patient Shows Similar Phenotype in Experimental Infection","volume":"7","author":"Khanra","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1128\/EC.00152-06","article-title":"Modulation of Leishmania ABC protein gene expression through life stages and among drug-resistant parasites","volume":"5","author":"Leprohon","year":"2006","journal-title":"Eukaryot. Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1128\/AAC.01023-13","article-title":"Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by leishmania subgenus viannia species","volume":"58","author":"Obonaga","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/0035-9203(94)90106-6","article-title":"Aminosidine and its combination with sodium stibogluconate in the treatment of diffuse cutaneous leishmaniasis caused by leishmania aethiopica","volume":"88","author":"Teklemariam","year":"1994","journal-title":"Trans. R. Soc. Trop. Med. Hyg."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/11\/723\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:34Z","timestamp":1760189614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/11\/723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,11]]},"references-count":128,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["biom9110723"],"URL":"https:\/\/doi.org\/10.3390\/biom9110723","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,11]]}}}