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Identification of N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo[1,5-a]-quinolin-4-yl)-1,3,4-thiadiazol-2-yl) acetamide derivatives as potential caspase-3 inhibitors via detailed computational investigations

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Abstract

The current study included density function theory calculations, molecular docking studies, SeeSAR analysis, molecular dynamics studies and assessments of the absorption, distribution, metabolism, excretion and toxicity properties (ADMET) of N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo[1,5-a] acetamides of -quinolin-4-yl)-1,3,4-thiadiazol-2-yl) that is 4a-j. These derivatives have previously been identified as anticancer agents against a human cervical cancer cell line. The primary goal of this work is to assess the potential of these derivatives as caspase-3 inhibitors using extensive computational analysis. The binding interactions of these compounds with caspase-3 protein (PDB ID: 4JJ8) were found and all compounds demonstrated strong binding interactions within the active pocket of the targeted protein. Interestingly, derivative 4e showed maximum potential and was found to have the strongest interactions with a binding energy of −29.6 kJ/mol. Furthermore, the findings were discovered to be in comparison with the reference drug, adriamycin (−26.5 kJ/mol). In addition to molecular docking, ADMET and simulation studies were carried out to determine their safety profiles, with the results correlating to molecular docking investigations. Finally, SeeSAR analysis and molecular dynamics simulation investigations were carried out. In conclusion, this molecule may be a “lead candidate’ for making a more powerful caspase-3 inhibitor that can be used in tumors where the levels of caspase-3 are aberrantly high.

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ChemDraw Ultra 12.0, Gaussian 09, GaussView 5.0, Discovery Studio (2020).

Change history

  • 02 July 2022

    Springer Nature’s version of this paper was updated: The name of the University in the Acknowledgements was changed from “Abdul Rahman“ to “Abdulrahman”.

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Acknowledgements

All authors are thankful to Marganakop and his co-workers for compounds data. We acknowledge Princess Nourah Bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R116), Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan

    Syeda Abida Ejaz, Mubashir Aziz, Amna Saeed, Hafiz Mohammad Kashif Mahmood & Ammara Fayyaz

  2. Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia

    Aisha A. Alsfouk

  3. Department of Pharmacology and Therapeutics, Faculty of Veternary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt

    Gaber El-Saber Batiha

  4. Department of Chemistry, Mississippi State University, Starkville, USA

    Abdullahi Tunde Aborode

  5. Department of Physics, The Government Sadiq College Women University, Bahawalpur, 63100, Pakistan

    Syeda Rabia Ejaz

  6. Molecular Biology and Bioinformatics Laboratory, Department of Biochemistry, Federal University of Technology, PMB 704, Akure, Ondo State, Nigeria

    Haruna Isiyaku Umar

  7. Computer-Aided Therapeutic Discovery and Design Group, Akure, Akure, Nigeria

    Haruna Isiyaku Umar

Authors
  1. Syeda Abida Ejaz
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Contributions

S. A. E. and A. A. A. devised and supervised the study plan. M. A., A. S., and A. F. carried out the molecular docking investigations under the direction of G. S. B and A. T. A. The MD simulations and DFTs were performed by S. R. E and H. M. K. The manuscript write up was carried out by S. A. E, M. A, and H. I. U. All authors read and approved the manuscript for publication.

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Correspondence to Syeda Abida Ejaz.

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Ejaz, S.A., Alsfouk, A.A., Batiha, G.ES. et al. Identification of N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo[1,5-a]-quinolin-4-yl)-1,3,4-thiadiazol-2-yl) acetamide derivatives as potential caspase-3 inhibitors via detailed computational investigations. Struct Chem 34, 425–438 (2023). https://doi.org/10.1007/s11224-022-01986-0

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