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

Document Type : Original Article

Authors

1 Department of Chemistry, Faculty of Physical Science, Ahmadu Bello University, P.M.B 1045, Zaria, Kaduna State, Nigeria.

2 Department of Chemistry, Faculty of Science, Air force Institute of Technology, P.M.B 2104, Kaduna State, Nigeria.

3 Department of Chemistry, Faculty of Science, Air force Institute of Technology, P.M.B 2104, Kaduna State, Nigeria

Abstract

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.

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Main Subjects

References

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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.
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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.
Journal of Epigenetics
Volume 6, Issue 1
June 2025
Pages 47-63

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History

  • Receive Date: 27 February 2025
  • Revise Date: 09 March 2025
  • Accept Date: 27 April 2025

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