{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T13:11:12Z","timestamp":1760965872010,"version":"build-2065373602"},"reference-count":94,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"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>Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1\u03b4) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1\u03b4 using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1\u03b4 (\u221246.53\u00b11.94 kcal\/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood\u2013brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1\u03b4 inhibitors for future experimental validation in the treatment of ALS.<\/jats:p>","DOI":"10.3390\/ijms262010188","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T12:27:29Z","timestamp":1760963249000},"page":"10188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Casein Kinase 1\u03b4 as a Novel Therapeutic Strategy for Amyotrophic Lateral Sclerosis: A Theoretical Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9020-7659","authenticated-orcid":false,"given":"Albert Gabriel","family":"Turpo-Peqque\u00f1a","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Medicina Humana, Centro de Investigaci\u00f3n y Estudios M\u00e9dicos (CIEM), Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Arequipa 04013, Peru"},{"name":"Facultad de Biolog\u00eda, Universidad Nacional de San Agust\u00edn, Av. Alcides Carri\u00f3n s\/n, Arequipa 04000, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9033-9950","authenticated-orcid":false,"given":"Renato Javier","family":"Valencia-Arce","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3727-1445","authenticated-orcid":false,"given":"Fabio Leonardo","family":"Del-Carpio-Carrazco","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5480-0347","authenticated-orcid":false,"given":"David Jonatan","family":"Quispe-Ppacco","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9872-4238","authenticated-orcid":false,"given":"Pierina Fernanda","family":"Carbajal-Llerena","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1511-9229","authenticated-orcid":false,"given":"Harlly Romed","family":"Loza-Chipa","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Medicina Humana, Centro de Investigaci\u00f3n y Estudios M\u00e9dicos (CIEM), Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6611-390X","authenticated-orcid":false,"given":"Antonella Sofia","family":"V\u00e1squez-Macedo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-1207","authenticated-orcid":false,"given":"Badhin","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2013CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n, Umacollo, Arequipa 04013, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Van Schependom, J., and D\u2019haeseleer, M. (2023). Advances in Neurodegenerative Diseases. J. Clin. Med., 12.","DOI":"10.3390\/jcm12051709"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1001\/jamaneurol.2019.2044","article-title":"Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis","volume":"76","author":"Ryan","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_3","first-page":"96","article-title":"Gene discovery in amyotrophic lateral sclerosis: Implications for clinical management","volume":"13","author":"Veldink","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40035-021-00250-5","article-title":"A perspective on therapies for amyotrophic lateral sclerosis: Can disease progression be curbed?","volume":"10","author":"Xu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_5","first-page":"1","article-title":"Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012\u20132013","volume":"65","author":"Mehta","year":"2016","journal-title":"Morb. Mortal. Wkly. Rep. Surveill. Summ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1750-1326-8-28","article-title":"Genetics of amyotrophic lateral sclerosis: An update","volume":"8","author":"Chen","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1212\/WNL.0b013e3181b6bbbd","article-title":"ALS motor phenotype heterogeneity, focality, and spread: Deconstructing motor neuron degeneration","volume":"73","author":"Ravits","year":"2009","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"ref_9","first-page":"57","article-title":"Variation in worldwide incidence of amyotrophic lateral sclerosis: A meta-analysis","volume":"46","author":"Marin","year":"2016","journal-title":"Int. J. Epidemiol."},{"key":"ref_10","first-page":"e45489","article-title":"Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects","volume":"15","author":"Hoxhaj","year":"2023","journal-title":"Cureus"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1001\/archneur.63.8.1139","article-title":"Slower Disease Progression and Prolonged Survival in Contemporary Patients With Amyotrophic Lateral Sclerosis: Is the Natural History of Amyotrophic Lateral Sclerosis Changing?","volume":"63","author":"Czaplinski","year":"2006","journal-title":"Arch. Neurol."},{"key":"ref_12","unstructured":"Brotman, R.G., Moreno-Escobar, M.C., Joseph, J., Munakomi, S., and Pawar, G. (2025). Amyotrophic Lateral Sclerosis, StatPearls."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1038\/s41467-024-48488-7","article-title":"TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression","volume":"15","author":"Fathi","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1093\/brain\/awae078","article-title":"Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models","volume":"147","author":"Droppelmann","year":"2024","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eadf6895","DOI":"10.1126\/sciadv.adf6895","article-title":"Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis","volume":"9","author":"Oiwa","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/s12276-020-00513-7","article-title":"The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies","volume":"52","author":"Jo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e10622","DOI":"10.15252\/emmm.201910622","article-title":"HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies","volume":"12","author":"Wu","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ko, V.I., Ong, K., Cleveland, D.W., Yu, H., and Ravits, J.M. (2024). CK1\u03b4\/\u03b5 kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation. Neurobiol. Dis., 196.","DOI":"10.1016\/j.nbd.2024.106516"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/hmg\/ddt498","article-title":"TDP-43 Phosphorylation by casein kinase I\u03b5 promotes oligomerization and enhances toxicity in vivo","volume":"23","author":"Choksi","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1007\/s11064-019-02832-2","article-title":"Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells","volume":"45","author":"Hicks","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16208","DOI":"10.1523\/JNEUROSCI.2911-10.2010","article-title":"Phosphorylation Promotes Neurotoxicity in aCaenorhabditis elegansModel of TDP-43 Proteinopathy","volume":"30","author":"Liachko","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Gonz\u00e1lez, L., Rodr\u00edguez-Cueto, C., Cabezudo, D., Bartolom\u00e9, F., Andr\u00e9s-Benito, P., Ferrer, I., Gil, C., Mart\u00edn-Requero, \u00c1., Fern\u00e1ndez-Ruiz, J., and Mart\u00ednez, A. (2020). Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1\u03b4 kinase inhibitor treatment. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-61265-y"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/s13197-022-05594-y","article-title":"Molecular dynamic (in silico) modeling of structure-function of glutelin type-B 5-like from proso millet storage protein: Effects of temperature and pressure","volume":"60","author":"Akharume","year":"2022","journal-title":"J. Food Sci. Technol."},{"key":"ref_24","unstructured":"Chaikuad, A., Arrowsmith, C., Edwards, A., Bountra, C., Roush, W., and Knapp, S. (2025, October 15). Crystal Structure of Casein Kinase 1 Delta (CK1 Delta) Complexed with SR3029 Inhibitor: 6rcg. Available online: https:\/\/www.rcsb.org\/structure\/6RCG."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5.6.1\u20135.6.37","DOI":"10.1002\/cpbi.3","article-title":"Comparative Protein Structure Modeling Using MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W374","DOI":"10.1093\/nar\/gky380","article-title":"CavityPlus: A web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction","volume":"46","author":"Xu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1021\/acs.jctc.2c01145","article-title":"Uni-Dock: GPU-Accelerated Docking Enables Ultralarge Virtual Screening","volume":"19","author":"Yu","year":"2023","journal-title":"J. Chem. Theory Comput."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1002\/1521-3773(20020802)41:15<2644::AID-ANIE2644>3.0.CO;2-O","article-title":"Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors","volume":"41","author":"Gohlke","year":"2002","journal-title":"Angew. Chem. (Int. Ed. Engl.)"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the Performance of the MM\/PBSA and MM\/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations","volume":"51","author":"Hou","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models","volume":"33","author":"Kollman","year":"2000","journal-title":"Accounts Chem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Knippschild, U., Kr\u00fcger, M., Richter, J., Xu, P., Garc\u00c3 a-Reyes, B., Peifer, C., Halekotte, J., Bakulev, V., and Bischof, J. (2014). The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis. Front. Oncol., 4.","DOI":"10.3389\/fonc.2014.00096"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1021\/jm201387s","article-title":"Structural Basis for the Interaction between Casein Kinase 1 Delta and a Potent and Selective Inhibitor","volume":"55","author":"Long","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"C\u00f3rdova-Bahena, L., S\u00e1nchez-\u00c1lvarez, A.A., Ruiz-Moreno, A.J., and Velasco-Vel\u00e1zquez, M.A. (2021). Repositioning of Etravirine as a Potential CK1\u03b5 Inhibitor by Virtual Screening. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010008"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sunkari, Y.K., Meijer, L., and Flajolet, M. (2022). The protein kinase CK1: Inhibition, activation, and possible allosteric modulation. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.916232"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e4792","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: Tools for structure building and analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1124\/jpet.109.151415","article-title":"Selective Inhibition of Casein Kinase 1\u03b5 Minimally Alters Circadian Clock Period","volume":"330","author":"Walton","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Joshi, K., Goyal, S., Grover, S., Jamal, S., Singh, A., Dhar, P., and Grover, A. (2016). Novel group-based QSAR and combinatorial design of CK-1\u03b4 inhibitors as neuroprotective agents. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-1379-9"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00726-012-1234-x","article-title":"2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1\u03b4\/\u03b5","volume":"43","author":"Bischof","year":"2012","journal-title":"Amino Acids"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Halekotte, J., Witt, L., Ianes, C., Kr\u00fcger, M., B\u00fchrmann, M., Rauh, D., Pichlo, C., Brunstein, E., Luxenburger, A., and Baumann, U. (2017). Optimized 4,5-Diarylimidazoles as Potent\/Selective Inhibitors of Protein Kinase CK1\u03b4 and Their Structural Relation to p38\u03b1 MAPK. Molecules, 22.","DOI":"10.3390\/molecules22040522"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1021\/acs.jmedchem.8b00095","article-title":"Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) \u03b4\/\u03b5","volume":"61","author":"Witt","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4374","DOI":"10.1016\/j.bmcl.2013.05.075","article-title":"Development of highly selective casein kinase 1\u03b4\/1\u03b5 (CK1\u03b4\/\u03b5) inhibitors with potent antiproliferative properties","volume":"23","author":"Bibian","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/sj.embor.7400048","article-title":"D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a","volume":"5","author":"Rena","year":"2004","journal-title":"EMBO Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7395","DOI":"10.1111\/jcmm.16767","article-title":"Csnk1a1 inhibition modulates the inflammatory secretome and enhances response to radiotherapy in glioma","volume":"25","author":"Liu","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"E7522","DOI":"10.1073\/pnas.1802422115","article-title":"Tumor promoter TPA activates Wnt\/\u03b2-catenin signaling in a casein kinase 1-dependent manner","volume":"115","author":"Su","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1182\/blood-2020-142557","article-title":"Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS","volume":"136","author":"Ball","year":"2020","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cunningham, P.S., Ahern, S.A., Smith, L.C., da Silva Santos, C.S., Wager, T.T., and Bechtold, D.A. (2016). Targeting of the circadian clock via CK1\u03b4\/\u03b5 to improve glucose homeostasis in obesity. Sci. Rep., 6.","DOI":"10.1038\/srep29983"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1021\/cn500201x","article-title":"Casein Kinase 1\u03b4\/\u03b5 Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior","volume":"5","author":"Wager","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3390\/md20080026","article-title":"Anticancer Alkaloid Lamellarins Inhibit Protein Kinases","volume":"6","author":"Trinkler","year":"2008","journal-title":"Mar. Drugs"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.bmc.2017.12.020","article-title":"Development of dual casein kinase 1\u03b4\/1\u03b5 (CK1\u03b4\/\u03b5) inhibitors for treatment of breast cancer","volume":"26","author":"Monastyrskyi","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1016\/j.bmcl.2012.07.046","article-title":"2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1\u03b3) inhibitors","volume":"22","author":"Hua","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15240","DOI":"10.1073\/pnas.1005101107","article-title":"Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes","volume":"107","author":"Meng","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3383","DOI":"10.1021\/acs.jproteome.9b00312","article-title":"Therapeutic Targeting of Casein Kinase 1\u03b4\/\u03b5 in an Alzheimer\u2019s Disease Mouse Model","volume":"18","author":"Adler","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1124\/jpet.107.122846","article-title":"An Inhibitor of Casein Kinase I\u03b5 Induces Phase Delays in Circadian Rhythms under Free-Running and Entrained Conditions","volume":"322","author":"Badura","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1038\/onc.2010.627","article-title":"IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1\u03b4\/\u03b5 and Wnt\/\u03b2-catenin independent inhibition of mitotic spindle formation","volume":"30","author":"Cheong","year":"2011","journal-title":"Oncogene"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Sundaram, S., Nagaraj, S., Mahoney, H., Portugues, A., Li, W., Millsaps, K., Faulkner, J., Yunus, A., Burns, C., and Bloom, C. (2019). Inhibition of casein kinase 1\u03b4\/\u03b5improves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer\u2019s disease. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-50197-x"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e00172","DOI":"10.1002\/pld3.172","article-title":"Structure-function study of a novel inhibitor of the casein kinase 1 family inArabidopsis thaliana","volume":"3","author":"Saito","year":"2019","journal-title":"Plant Direct"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13024-016-0102-7","article-title":"Targeting TDP-43 phosphorylation by Casein Kinase-1\u03b4 inhibitors: A novel strategy for the treatment of frontotemporal dementia","volume":"11","author":"Alquezar","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1021\/acsomega.7b00869","article-title":"Biological and Pharmacological Characterization of Benzothiazole-Based CK-1\u03b4 Inhibitors in Models of Parkinson\u2019s Disease","volume":"2","author":"Salado","year":"2017","journal-title":"ACS Omega"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1007\/s12035-018-1249-8","article-title":"Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients","volume":"56","author":"Posa","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Martinez-Gonzalez, L., Cuevas, E.P., Tosat-Bitri\u00e1n, C., Nozal, V., Gil, C., Palomo, V., Mart\u00edn-Requero, \u00c1., and Martinez, A. (2023). TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer\u2019s disease patients. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1243277"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10608","DOI":"10.1002\/anie.201103915","article-title":"A Small Molecule Modulates Circadian Rhythms through Phosphorylation of the Period Protein","volume":"50","author":"Lee","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7933","DOI":"10.1021\/jm500600b","article-title":"Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1\u03b4 and \u03b5 with Nanomolar Inhibitory Activity on Cancer Cell Proliferation","volume":"57","author":"Richter","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1074-5521(00)00063-6","article-title":"Inhibition of cyclin-dependent kinases, GSK-3\u03b2 and CK1 by hymenialdisine, a marine sponge constituent","volume":"7","author":"Meijer","year":"2000","journal-title":"Chem. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1039\/C4OB00091A","article-title":"Callyspongisines A-D: Bromopyrrole alkaloids from an Australian marine sponge, Callyspongia sp","volume":"12","author":"Plisson","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.chembiol.2004.01.015","article-title":"Synthesis and Target Identification of Hymenialdisine Analogs","volume":"11","author":"Wan","year":"2004","journal-title":"Chem. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1016\/j.tetlet.2012.05.051","article-title":"A search for kinase inhibitors and antibacterial agents: Bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge, Axinella sp","volume":"53","author":"Zhang","year":"2012","journal-title":"Tetrahedron Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5672","DOI":"10.1016\/j.bmcl.2008.08.072","article-title":"Identification of novel protein kinase CK1 delta (CK1\u03b4) inhibitors through structure-based virtual screening","volume":"18","author":"Cozza","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/prot.24350","article-title":"Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics: Proline Force Field Parameters","volume":"82","author":"Aliev","year":"2013","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1093\/bioinformatics\/btr168","article-title":"ProDy: Protein Dynamics Inferred from Theory and Experiments","volume":"27","author":"Bakan","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_73","first-page":"D520","article-title":"Protein Data Bank: The single global archive for 3D macromolecular structure data","volume":"47","author":"Burley","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Burley, S.K., Berman, H.M., Kleywegt, G.J., Markley, J.L., Nakamura, H., and Velankar, S. (2017). Protein Data Bank (PDB): The Single Global Macromolecular Structure Archive. Protein Crystallography, Springer.","DOI":"10.1007\/978-1-4939-7000-1_26"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"D668","DOI":"10.1093\/nar\/gkj067","article-title":"DrugBank: A comprehensive resource for in silico drug discovery and exploration","volume":"34","author":"Wishart","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13321-020-00469-w","article-title":"DECIMER: Towards deep learning for chemical image recognition","volume":"12","author":"Rajan","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_78","unstructured":"Landrum, G., Tosco, P., Kelley, B., Rodriguez, R., Cosgrove, D., Vianello, R., Gedeck, P., Jones, G., and Kawashima, E. (2025, October 15). rdkit\/rdkit: 2025_03_4 (Q1 2025) Release. Available online: https:\/\/zenodo.org\/records\/15773589."},{"key":"ref_79","unstructured":"Van Rossum, G., and Drake, F. (2009). Python 3 Reference Manual: (Python Documentation Manual Part 2), CreateSpace Independent Publishing Platform. Documentation for Python."},{"key":"ref_80","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_81","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.1021\/acs.jcim.3c01153","article-title":"AmberTools","volume":"63","author":"Case","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"W331","DOI":"10.1093\/nar\/gkx312","article-title":"LigParGen web server: An automatic OPLS-AA parameter generator for organic ligands","volume":"45","author":"Dodda","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cplett.2004.06.011","article-title":"A new hybrid exchange-correlation functional using the Coulomb-attenuating method (CAM-B3LYP)","volume":"393","author":"Yanai","year":"2004","journal-title":"Chem. Phys. Lett."},{"key":"ref_85","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. (2016). Gaussian~16 Revision C.01, Gaussian Inc."},{"key":"ref_86","unstructured":"Abraham, M., Alekseenko, A., Basov, V., Bergh, C., Briand, E., Brown, A., Doijade, M., Fiorin, G., Fleischmann, S., and Gorelov, S. (2025, October 15). GROMACS 2024.5 Manual. Available online: https:\/\/manual.gromacs.org\/documentation\/2024.5\/install-guide\/index.html."},{"key":"ref_87","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_88","doi-asserted-by":"crossref","unstructured":"Rooijers, K., Kolmeder, C., Juste, C., Dor\u00e9, J., de Been, M., Boeren, S., Galan, P., Beauvallet, C., de Vos, W.M., and Schaap, P.J. (2011). An iterative workflow for mining the human intestinal metaproteome. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-6"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Sang, P., Yang, Q., Du, X., Yang, N., Yang, L.Q., Ji, X.L., Fu, Y.X., Meng, Z.H., and Liu, S.Q. (2016). Effect of the Solvent Temperatures on Dynamics of Serine Protease Proteinase K. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020254"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/pro.3280","article-title":"Improvements to the APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2017","journal-title":"Protein Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa-A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_92","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.","DOI":"10.1007\/978-94-015-7658-1_21"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1093\/bioinformatics\/13.4.425","article-title":"Objectively judging the quality of a protein structure from a Ramachandran plot","volume":"13","author":"Hooft","year":"1997","journal-title":"Bioinformatics"},{"key":"ref_94","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."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T12:28:21Z","timestamp":1760963301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,20]]},"references-count":94,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms262010188"],"URL":"https:\/\/doi.org\/10.3390\/ijms262010188","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,20]]}}}