Drug targeting to folate receptor alpha (FRα) has received significant attention in the area of cancer drug delivery. In this study, we designed folic acid (FA) derivatives as well as conjugated them to beta-cyclodextrin (βCD) and subjected to <i>in silico</i> analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability towards FRα. Docking studies revealed twenty of the designed compounds and the conjugated FA bound into the active site of FRα with higher affinity than FA (free binding energy &lt;-15 kcal/mol), with a similar binding pose to that of FA. Subsequent analyses from molecular dynamics (MD) simulations demonstrated that FA and FA-βCD created more dynamically stable systems with FRα than apo-FRα system. The conjugation with βCD improved the stability and decreased the mobility for all the residues (except the residues 149-151) compared to FA-FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA) and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

Conjugation with β-cyclodextrin and structural derivatization of folic acid enhances affinity towards folate receptor alpha: Molecular dynamics study

ACS Spring 2022

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