Novel group-based QSAR and combinatorial design of CK-1δ inhibitors as neuroprotective agents

BMC Bioinformatics

Research

Kopal Joshi¹  Salma Jamal²  Sukriti Goyal²  Aditi Singh³  Sonam Grover⁴  Pawan Dhar⁵  Abhinav Grover⁵ 

[1] Amity School of Biotechnology, Amity University, 201303, Noida, Uttar Pradesh, India;Department of Bioscience and Biotechnology, Banasthali University, 304022, Tonk, Rajasthan, India;Department of Biotechnology, TERI University, 110070, New Delhi, India;Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, 110016, New Delhi, India;School of Biotechnology, Jawaharlal Nehru University, 110067, New Delhi, India;

关键词: Amyotrophic lateral sclerosis;    ALS;    TDP-43;    Casein kinase;    QSAR;    Combinatorial library;   

DOI  :  10.1186/s12859-016-1379-9

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2016

【 图 表 】

12951_2017_315_Article_IEq1.gif

Fig. 1

12951_2015_155_Article_IEq23.gif

12951_2015_155_Article_IEq22.gif

12951_2015_155_Article_IEq21.gif