Novel group-based QSAR and combinatorial design of CK-1δ inhibitors as neuroprotective agents. Issue 19 (December 2016)

• Record Type: Journal Article
• Authors: Joshi, Kopal; Goyal, Sukriti; Grover, Sonam; Jamal, Salma; Singh, Aditi; Dhar, Pawan; Grover, Abhinav
• Is Part Of: BMC bioinformatics. Volume 17:Issue 19(2016)
• Page Start: 283
• Page End: 295
• Publication Date: 2016-12
• Subjects: Amyotrophic lateral sclerosis -- ALS -- TDP-43 -- Casein kinase -- QSAR -- Combinatorial library; Bioinformatics -- Periodicals; Computational biology -- Periodicals; 570.285
• DOI: 10.1186/s12859-016-1379-9
• Languages: English
• ISSNs: 1471-2105

Abstract

Abstract Background 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 thus qualifies as a potential target for ALS treatment. Results The 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. Conclusions In 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.