Abstract:
The bioavailability of drugs and their distribution in the body depend on their interaction
with plasma proteins. Alpha-acid glycoprotein (AGP) is one of the major plasma proteins that
can bind to various basic and neutral molecules through its interactions. Our study focuses
on the mode of binding between AGP and these anticancer molecules: abemaciclib,
doxorubicin, elacestrant, epirubicin, pirtobrutinib, talazoparib, tucatinib et zanubrutinib.
To characterize this mechanism of interaction, in silico approaches were combined: molecular
docking (CB-DOCK 2) was used to predict key binding sites on AGP, BIOVIA Discovery
studio and Chimera were used to visualize the interactions of binary AGP-ligand complexes,
while analysis of molecular dynamics simulations (CAB-flex 2.0) assessed the stability
of the drug complexes via RMSF analysis.
The results obtained show favorable binding energies for all studied anticancer molecules
varied from -8 kcal/mol to Ŕ 11 kcal/mol, tucatinib show the best binding energy estimated
at (ΔG =-11kcal/mol), with interactions stabilized by residues Phe114, Arg90, Tyr37, Tyr127,
Tyr27, Ala99, Leu79, Val92 et Phe32. A molecular dynamics study using RMSF analysis also
showed that the binding of anti-cancer molecules to the AGP protein contributes to the stability
of its spatial structure.
In conclusion, this study highlights the importance of AGP in the pharmacokinetics
of anticancer drugs, and paves the way for personalized strategies to optimize their efficacy.
