Contribution à l’étude in silico de l’interaction entre alpha-1-acide glycoprotéine et de molécules anticancéreuses

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.