A quantitative structure-activity relationship (QSAR) study is performed on 48 novel 4,5,6,7-tetrahydrobenzo[D]thiazol-2 derivatives as anticancer agents capable of inhibiting c-Met receptor tyrosine kinase. The present study is conducted using multiple linear regression, multiple nonlinear regression and artificial neural networks. Three QSAR models are developed after partitioning the database into two sets (training and test) via the k-means method. The obtained values of the correlation coefficients by the three developed QSAR models are 0.90, 0.91 and 0.92, respectively. The resulting models are validated by using the external validation, leave-one-out crossvalidation, Y-randomization test, and applicability domain methods. Moreover, we evaluated the drug-likeness properties of seven selected molecules based on their observed high activity to inhibit the c-Met receptor. The results of the evaluation showed that three of the seven compounds present drug-like characteristics.In order to identify the important active sites for the inhibition of the c-Met receptor responsible for the development of cancer cell lines, the crystallized form of the Crizotinib-c-Met complex (PDB code: 2WGJ) is used. These sites are used as references in the molecular docking test of the three selected molecules to identify the most suitable molecule for use as a new c-Met inhibitor. A comparative study is conducted based on the evaluation of the predicted properties of ADMET in silico between the candidate molecule and the Crizotinib inhibitor. The comparison results show that the selected molecule can be used as new anticancer drug candidates.
Background:
One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase
inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients.
Objective:
The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal
chelation capacity, POM analyses and DFT studies respectively.
Method:
The cholinesterase inhibition and metal chelation ability was performed on ELISA microtiter assay. Whereas B3LYP
method with 6-31+G(d,p) basis set was implemented to study HOMO-LUMO energy calculations. The pharmacokinetic properties of
the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM).
Results:
The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed
that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be
the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation
capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE’s
active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information
about the flexibility at the site of coordination of spiro compounds (1-6).
Conclusion:
The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential
to inhibit AChE and BChE. Herein we propose that the spiro molecules after further derivatization could serve interesting AD
inhibitor drugs.
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