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QSAR, molecular docking and ADMET properties in silico studies of novel 4,5,6,7-tetrahydrobenzo[D]-thiazol-2-Yl derivatives derived from dimedone as potent anti-tumor agents through inhibition of C-Met receptor tyrosine kinase.

ABSTRACT: 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 cross-validation, 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.

SUBMITTER: Daoui O

PROVIDER: S-EPMC8282965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target.MethodsQuantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated.ResultsA robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from -8.200 to -10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target.ConclusionQSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.

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QSAR, molecular docking and ADMET properties in silico studies of novel 4,5,6,7-tetrahydrobenzo[D]-thiazol-2-Yl derivatives derived from dimedone as potent anti-tumor agents through inhibition of C-Met receptor tyrosine kinase.

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