In silico analysis of doxorubicin analogues conjugated to polysorbate 80 for sustained and targeted delivery to the brain

Drug discovery for the treatment of central nervous system (CNS) diseases is a highly complex affair, especially due to the blood brain barrier (BBB) restricting the entry of many drugs. In the present study, we utilized in silico studies to screen twelve derivatives of doxorubicin (DOX) against seven tumor proteins. The DOX ligands were modelled and optimized using Density Functional Theory (DFT), and the binding affinity was evaluated. Seven tumor proteins were selected for docking and their PDB IDs were: 3LGL, 2IG0, 3LGF, 4RG2, 3PG7, 3LH0 , and 4HBM . Later, an attempt was made to deliver these modified DOX ligands into the brain using a non-ionic surfactant, polysorbate 80 (PS80). Modified DOX ligands-PS80 conjugated structures were made using Semi empirical methods. After categorizing 12 DOX ligands and 12 DOX-PS80 conjugated ligands, the top-ranked three DOX ligands ( R6 , R4 , and R9 ) and their conjugates with PS80 ( R6-PS80 , R4-PS80 , and R9-PS80 ) underwent comprehensive molecular dynamics (MD) analysis. The best DOX ligands and their conjugated structures with PS80 were subjected to a thorough examination for structural stability (RMSD), intermolecular hydrogen bond (H-bond) interactions, effect of solvent accessibility (SASA), and compactness (Rg). The results demonstrated that these ligands and conjugated ligands exhibited folding behavior and were incredibly stable. Furthermore, we employed MM/GBSA to figure out the docking scores of the top three DOX-PS80-conjugated ligands. In silico pharmacokinetic parameters of all compounds were analyzed using the ADMET AI server. It is shown that attaching to PS80 could potentially decrease the overall toxicity of DOX ligands. These findings indicate that the modified DOX ligands, when combined with PS80, have the potential to cross the BBB and could be used for further in vitro and in vivo evaluation.