Althiabat, Mohammad Gasem Mohammad
(2024)
Derivatization And Conjugation Of Folic Acid To Improve Its Affinity Towards Folate Receptor Alpha On Cancerous Membrane Bilayer: An In Silico Insight.
PhD thesis, Perpustakaan Hamzah Sendut.
Abstract
Effective targeting of cancerous cells with minimal side effects remains a
significant challenge in the development of chemotherapeutic drugs. This study
presents a novel in silico approach for targeting chemotherapeutic drug delivery to
cancer cells using folic acid (FA) conjugated to β-cyclodextrin (βCD), aimed at
enhancing selectivity via the interaction with folate receptor alpha (FRα). In a previous
in silico study, enhanced targeting was demonstrated by tetrazole (FOL03) and
benzothiophene (FOL08) folic acid derivatives, with FOL03 exhibiting superior
affinity for FRα. In this study, molecular docking and molecular dynamics (MD)
simulations was employed to assess the impact of βCD on the binding affinity and
stability of FA, FOL03, and FOL08 conjugates with FRα. Additionally, replica
exchange umbrella sampling (REUS) was used to examine the retention of conjugates
and the chemotherapeutic agent 5-fluorouracil (FLU) within βCD's hydrophobic
cavity under virtual simulated cancerous conditions which also include the lipid
bilayer environment. In the non-inclusion systems, the docking scores show that FRα-
FOL08-βCD exhibited stronger binding (-17.10 kcal/mol) than -FA-βCD (-15.20
kcal/mol) and -FOL03-βCD (-15.50 kcal/mol). All ligands bound in a similar pose
within the active site of FRα. MD simulations over 100 ns demonstrated that the FRα-
FOL03-βCD complex maintained dynamic stability, showing minimal conformational
changes. Quantum mechanical analysis, using MOPAC-2016 and the PM7 method,
corroborated the MD simulations, identifying the electronic properties that confer
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stability to the FRα-FOL03-βCD complex.
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