Abstract
BackgroundTar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS). Among the reported isoforms and splice variants of CK-1 protein superfamily, CK-1δ is known to phosphorylate different serine and threonine sites on TDP-43 protein in vitro and thus qualifies as a potential target for ALS treatment.ResultsThe developed GQSAR (group based quantitative structure activity relationship) model displayed satisfactory statistical parameters for the dataset of experimentally reported N-Benzothiazolyl-2-Phenyl Acetamide derivatives. A combinatorial library of molecules was also generated and the activities were predicted using the statistically sound GQSAR model. Compounds with higher predicted inhibitory activity were screened against CK-1δ that resulted in to the potential novel leads for CK-1δ inhibition.ConclusionsIn this study, a robust fragment based QSAR model was developed on a congeneric set of experimentally reported molecules and using combinatorial library approach, a series of molecules were generated from which we report two top scoring, CK-1δ inhibitors i.e., CHC (6-benzyl-2-cyclopropyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}j-3-fluorophenyl hydrogen carbonate) and DHC (6-benzyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}-2-(decahydronaphthalen-1-yl)-3-hydroxyphenyl hydrogen carbonate) with binding energy of −6.11 and −6.01 kcal/mol, respectively.
Highlights
Tar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS)
Casein Kinase-1 (CK-1) was the first kinase that has been reported to cause this pathological phosphorylation of the TDP-43 protein and its activity has been found upregulated in spinal cord tissue in ALS and other neural disorders [12]
In this study, an attempt was made at creating a novel GQSAR model for the derivatives of N-Benzothiazolyl-2Phenyl Acetamide which act as inhibitors of Casein Kinase-1δ protein
Summary
Tar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS). Among the reported isoforms and splice variants of CK-1 protein superfamily, CK-1δ is known to phosphorylate different serine and threonine sites on TDP-43 protein in vitro and qualifies as a potential target for ALS treatment. Neuronal death is known to be caused in mice, zebrafish, worms, flies and monkeys due to the over expression of mutant TDP-43 It is believed the phosphorylation of TDP-43 may cause toxicity of the protein [1]. CK-1 isoforms are involved in regulation of circadian rhythms, Wnt signaling, nucleo-cytoplasmic shuttling of transcription factors, DNA transcription and DNA repair [16, 17] They have been found upregulated and mutated in various forms of cancer [18] and neurodegenative diseases. CK-1δ inhibition was found be beneficial in cancer inducing the DNA damage and significant role in pathological TDP-43 phosphorylation have been disclosed [20, 21]
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