Novel group-based QSAR and combinatorial design of CK-1δ inhibitors as neuroprotective agents.
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.
Amity School of Biotechnology, Amity University, Noida, Uttar Pradesh, 201303, India.
Kopal
K
Joshi
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, 304022, India.
Sukriti
S
Goyal
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, 110016, India.
Sonam
S
Grover
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, 304022, India.
Salma
S
Jamal
Department of Biotechnology, TERI University, New Delhi, 110070, India.
Aditi
A
Singh
School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
Pawan
P
Dhar
School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India. abhinavgr@gmail.com.
Abhinav
A
Grover
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000737:chemistry; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D004268:DNA-Binding Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; C000598624:TARDBP protein, human; D048148:Casein Kinase Idelta
ALS; Amyotrophic lateral sclerosis; Casein kinase; Combinatorial library; QSAR; TDP-43