Journal of Advanced Materials in Engineering

Journal of Advanced Materials in Engineering

Molecular Engineering of Mono-Chlorotriazinyl-Functionalized Betacyclodextrin-Based Nanocarriers for Targeted Methotrexate Delivery: A Molecular Docking and Dynamics Simulation Study

Articles in Press

Document Type : Original Article

Authors
Raziye Basiri 1
Parvin Asadi 2
Mohammad Dinari 1
1 Department of Chemistry, Isfahan University of Technology, Isfahan, Iran
2 1- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran 2- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Abstract
Introduction and Objectives: Betacyclodextrins, as drug carriers, increase the bioavailability of drugs. To enhance the stability of the complex and increase the aqueous solubility of poorly water-soluble drugs, the hydroxyl groups of the betacyclodextrin rings can be modified through chemical alterations. In this study, the interaction between the anticancer drug methotrexate and cyclodextrin, as well as cyclodextrin substituted with mono-chlorotriazinyl, was investigated via docking studies and molecular modeling.
Method: To determine the orientation and binding extent of methotrexate to cyclodextrin and to mono-chlorotriazinyl-substituted cyclodextrin, molecular docking calculations were performed using AutoDock 4.2 software. The study examined various positions of mono-chlorotriazinyl substitution on the cyclodextrin structure, and the best docked conformation obtained from the docking results was subjected to molecular dynamics simulations for 500 nanoseconds to assess the stability of the drug-carrier complex.
Results: The most favorable binding energy and conformer were for cyclodextrin bearing the mono-chlorotriazinyl substituent at glucose units 1, 2, and 5 (3-mct). Root mean square deviation plots and hydrogen-bond analyses derived from the molecular dynamics simulation of this complex, methotrexate was found to stabilize the complexes, and the complexes exhibited more negative van der Waals interaction energies compared to electrostatic interaction energies. Radius of gyration  for the complexed state was slightly lower than for the free state, attributed to water molecules leaving the cavity and the replacement of methotrexate within the mct cavity at a 1:1 ratio. Additionally, the 3-mct substituent increases the accessible surface area for solvent molecules due to its three mono-chlorotriazinyl groups.
Conclusion: Based on the docking and molecular dynamics simulations analyses, cyclodextrins bearing the mono-chlorotriazinyl substituent display a greater capability to interact with methotrexate than native cyclodextrin, forming a more stable complex over 500 nanoseconds of simulation. Therefore, this 3-mct substituted betacyclodextrin is recommended for experimental studies.
Keywords
Molecular dynamics simulation
Betacyclodextrin
Targeted drug delivery
Molecular docking
Methotrexate
Subjects
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Journal of Advanced Materials in Engineering

Articles in Press, Accepted Manuscript
Available Online from 02 May 2026

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