Computer-aided scaffold hopping to identify a novel series of casein kinase 1 delta (CK1d) inhibitors for amyotrophic lateral sclerosis

In this study as the first attempt; comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and AutoGPA-based 3D-QSAR methods were applied on a set of 47 recently reported Ck1d inhibitors, in order to gain an insight into the structural requirements which providing guidelines for the design of next generation compounds with enhanced bioactivity. The results of 3D-QSAR analyses indicated that hydrophobic and negatively charged groups at 6th position of benzothiazole ring and positively charged and bulky groups at ortho position of phenyl ring are favorable for high activity. Moreover, molecular docking studies with GOLD protocol revealed that this chemical series has two different orientations in CK1d active site: orientation 1, in which the benzothiazole ring of the compounds is the closet to the hydrophobic area created by Ile23 and 37, Ala36 Lys 38, Met80, 82 and Val81, and orientation 2, in which the benzene ring of the compounds is directed toward the hydrophobic center. Molecular docking result of the riluzole, the only drug approved by FDA for amyotrophic lateral sclerosis (ALS), indicated that the orientation 2 is preferred due to the presence of OCF3 group in R(1) situation at 6th position of benzothiazole ring, while with replacement of OCF3 group by CF3, the orientation 1 is observed. At the end, to find similar analogs by virtual screening, a two-stage approach: pharmacophore-based screening using generated AutoGPA-based 3D-QSAR model followed by structure-based virtual screening using molecular docking was employed. Visual inspection of the docking results of virtually obtained hits revealed two different binding orientations, in which compounds with high GOLD fitness scores produced binding modes, which were the same as the one observed in compounds with orientation 1, whereas the binding modes of the structures with low GOLD fitness scores were in agreement with orientation 2. Further, the drug-like properties of the obtained seven hits with the highest GOLD scores were investigated as a tool to optimize the selection of the most suitable candidates for drug development.

Amyotrophic lateral sclerosis; Casein kinase 1 delta (CK1d) inhibitors; Molecular docking; Pharmacophore; Virtual screening.