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New Piperidin-4-Amine Derivatives as Anti-HCV Inhibitors: A Structure-Based Approach Combining DFT, QSAR, and ADMET Analysis Targeting NS5B Polymerase eceived: date; Accepted | ||
| Journal of Epigenetics | ||
| مقاله 5، دوره 6، شماره 1، شهریور 2025، صفحه 47-63 اصل مقاله (1.11 M) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22111/jep.2025.51275.1081 | ||
| نویسندگان | ||
| Abubakar Sadiq Bello* 1؛ Adamu Uzairu2؛ Shallangwa Gideon .Adamu2؛ Abdulkadir Ibrahim3؛ Muhammad Tukur Ibrahim2 | ||
| 1Department of Chemistry, Faculty of Physical Science, Ahmadu Bello University, P.M.B 1045, Zaria, Kaduna State, Nigeria. | ||
| 2Department of Chemistry, Faculty of Science, Air force Institute of Technology, P.M.B 2104, Kaduna State, Nigeria. | ||
| 3Department of Chemistry, Faculty of Science, Air force Institute of Technology, P.M.B 2104, Kaduna State, Nigeria | ||
| چکیده | ||
| Hepatitis C virus (HCV) is a major cause of severe liver disease, leading to complications such as cirrhosis, liver failure, and hepatocellular carcinoma, liver damage, and basic cancer of the liver (hepatocellular carcinoma). There have been major therapeutic advances since the virus's discovery. Recent research has shown that plant-derived compounds are increasingly valuable in the development of innovative, effective, and cost-effective anti-Hepatitis C Virus treatments. In the current work, a complete examination of 31 piperidin derivatives was performed, these molecules were computationally examined using a through in-silico technique that includes 2D-3D Quantitative Structure Activity Relationship (QSAR) simulation and docking of molecular structures, and their properties were confirmed using ADMET and Density Functional Theory (DFT) calculations. The anti-hepatitis C compounds have been optimized utilizing the DFT approach using the B3LYP version and 6-31G* basis set. The Genetic Function Algorithm (GFA) was utilized to develop five models. An externally verified test set, Y-randomization, variance inflation factor (VIF), mean effect (MF), and William's plot applicability domain (AD) were used to build and validate a credible 2D QSAR model (R2 internal = 0.8537, R2 external = 0.6979). Compound 26 was the most promising candidate because of its remarkable binding affinity, which was demonstrated by the high molecular docking score of -142.24 kcal/mol that was obtained from the virtual screening of the compounds under investigation. A structure-based approach created six new molecules with increased affinity for the NS5B polymerase (SCD6 -153.74 kcal/mol). The newly discovered compounds have higher mole dock ratings than the FDA medicine Rib/Pig (-111.095 kcal/mol). According to the predicted drug-likeness and ADMET features, the most recently found compounds have a bioavailability value of 0.17, are easily synthesized in the wet laboratory (based on the synthetic accessibility value), and have favorable pharmacokinetic profiles. The developed molecule SCD6, which is stable, has greater affinity, and has the best pharmacokinetic features, should be produced in the wet lab as prospective Hepatitis C viral agents. | ||
| کلیدواژهها | ||
| Hepatitis C؛ NS-5B Polymerase؛ ADMET properties؛ Molecular docking؛ QSAR؛ Molecular Design؛ Pharmacokinetics | ||
| مراجع | ||
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El Kalai, F., Chelfi, T., Benchat, N., Hacht, B., Bouklah, M., Elaatiaoui, A., et al. (2019). New organic extractant based on pyridazinone scaffold compounds: Liquid-liquid extraction study and DFT calculations, Journal of Molecular Structure, 1191, 24-31.
Fukui, K. (1982). Role of frontier orbitals in chemical reactions, Science, 218(4574), 747-754.
Gázquez, J. L. (1993). Hardness and softness in density functional theory, Chemical hardness, 27-43.
Ibrahim, M. T., Tabti, K., Abdulsalam, S., Tahir, A. S., Mahmoud, A., and Danmallam, A. M. (2024). Discovery of new 2, 4-diaminopyrimidines derivatives as EGFRT790M kinase inhibitors: a structure-based approach with DFT calculation, drug-likeness, ADME-toxicity properties evaluation and MD simulation, Journal of Umm Al-Qura University for Applied Sciences, 1-17.
Ismail, S. Y., and Uzairu, A. (2019). In silico QSAR and molecular docking studies of sulfur containing shikonin oxime derivatives as anti-cancer agent for colon cancer, Radiology of Infectious Diseases, 6(3), 108-121.
Muhammad, U., Uzairu, A., and Ebuka Arthur, D. (2018). Review on: quantitative structure activity relationship (QSAR) modeling, J Anal Pharm Res, 7(2), 240-242.
Nulamuga, B., Uzairu, A., Babalola, I. T., Ibrahim, M. T., and Umar, A. B. (2023). In silico analysis of noscapine compounds as anti-tumor agents targeting the tubulin receptor, Journal of Taibah University Medical Sciences, 18(1), 32.
Olasupo, S. B., Uzairu, A., Shallangwa, G., and Uba, S. (2019). QSAR analysis and molecular docking simulation of norepinephrine transporter (NET) inhibitors as anti-psychotic therapeutic agents, Heliyon, 5(10).
Thomsen, R., and Christensen, M. H. (2006). MolDock: a new technique for high-accuracy molecular docking, Journal of medicinal chemistry, 49(11), 3315-3321.
Wolinski, K., Hinton, J. F., and Pulay, P. (1990). Efficient implementation of the gauge-independent atomic orbital method for NMR chemical shift calculations, Journal of the American Chemical Society, 112(23), 8251-8260. | ||
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