Obaid Afzal, Ali Altharawi, Safar M. Alqahtani, Manal A. Alossaimi, Taibah Aldakhil, Abdulmalik S. A. Altamimi, Alhumaidi Alabbas, Mubarak A. Alamri
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The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of <b>3</b>, <b>4b</b>, <b>4c</b> and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for <b>4c</b> and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds <b>3</b> (IC<sub>50</sub> 0.026 µM) and <b>4c</b> (IC<sub>50</sub> 0.048 µM) as compared to SNS-032 (IC<sub>50</sub> 0.052 µM) against CDK2, compounds <b>3</b> (IC<sub>50</sub> 0.315 µM), <b>4a</b> (IC<sub>50</sub> 0.248 µM), <b>4b</b> (IC<sub>50</sub> 0.276 µM), and <b>4c</b> (IC<sub>50</sub> 0.338 µM) as compared to SNS-032 (IC<sub>50</sub> 0.476 µM) against CDK5, compounds <b>3</b> (IC<sub>50</sub> 0.221 µM), <b>4a</b> (IC<sub>50</sub> 0.256 µM), <b>4b</b> (IC<sub>50</sub> 0.282 µM), <b>4c</b> (IC<sub>50</sub> 0.236 µM), and <b>4e</b> (IC<sub>50</sub> 0.274 µM) as compared to SNS-032 (IC<sub>50</sub> 0.365 µM) against CDK6, and comparable potency of compound <b>4b</b> (IC<sub>50</sub> 0.136 µM) with Sorafenib (IC<sub>50</sub> 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (<b>3</b> and <b>4a–f</b>) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.</p><h3>Graphical abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors\",\"authors\":\"Obaid Afzal, Ali Altharawi, Safar M. Alqahtani, Manal A. Alossaimi, Taibah Aldakhil, Abdulmalik S. A. Altamimi, Alhumaidi Alabbas, Mubarak A. 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MD simulations (100 ns) in the TIP3P water model for <b>4c</b> and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds <b>3</b> (IC<sub>50</sub> 0.026 µM) and <b>4c</b> (IC<sub>50</sub> 0.048 µM) as compared to SNS-032 (IC<sub>50</sub> 0.052 µM) against CDK2, compounds <b>3</b> (IC<sub>50</sub> 0.315 µM), <b>4a</b> (IC<sub>50</sub> 0.248 µM), <b>4b</b> (IC<sub>50</sub> 0.276 µM), and <b>4c</b> (IC<sub>50</sub> 0.338 µM) as compared to SNS-032 (IC<sub>50</sub> 0.476 µM) against CDK5, compounds <b>3</b> (IC<sub>50</sub> 0.221 µM), <b>4a</b> (IC<sub>50</sub> 0.256 µM), <b>4b</b> (IC<sub>50</sub> 0.282 µM), <b>4c</b> (IC<sub>50</sub> 0.236 µM), and <b>4e</b> (IC<sub>50</sub> 0.274 µM) as compared to SNS-032 (IC<sub>50</sub> 0.365 µM) against CDK6, and comparable potency of compound <b>4b</b> (IC<sub>50</sub> 0.136 µM) with Sorafenib (IC<sub>50</sub> 0.114 µM) against VEGFR2. 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Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors
The inhibition of cyclin-dependent kinases is a viable anticancer therapy due to their critical function in regulating cell cycle progression and transcription. The present study intended to design novel benzothiazolyl piperidine-3-carboxamide derivatives as multi-target CDKs and VEGFR2 inhibitor. Novel benzothiazolyl piperidine-3-carboxamide derivatives varying smaller and bulkier N-substitution at piperidine motif (4a–f) were designed based on the key structural features of SNS-032 (a CDK and VEGFR2 inhibitor). The compounds were subjected to extra-precision docking on seven CDKs and VEGFR2 kinase targets. The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of 3, 4b, 4c and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for 4c and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds 3 (IC50 0.026 µM) and 4c (IC50 0.048 µM) as compared to SNS-032 (IC50 0.052 µM) against CDK2, compounds 3 (IC50 0.315 µM), 4a (IC50 0.248 µM), 4b (IC50 0.276 µM), and 4c (IC50 0.338 µM) as compared to SNS-032 (IC50 0.476 µM) against CDK5, compounds 3 (IC50 0.221 µM), 4a (IC50 0.256 µM), 4b (IC50 0.282 µM), 4c (IC50 0.236 µM), and 4e (IC50 0.274 µM) as compared to SNS-032 (IC50 0.365 µM) against CDK6, and comparable potency of compound 4b (IC50 0.136 µM) with Sorafenib (IC50 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (3 and 4a–f) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.
期刊介绍：
The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas:
- theoretical chemistry;
- computational chemistry;
- computer and molecular graphics;
- molecular modeling;
- protein engineering;
- drug design;
- expert systems;
- general structure-property relationships;
- molecular dynamics;
- chemical database development and usage.
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