Binding of the anticancer drug BI-2536 to human serum albumin. A spectroscopic and theoretical study

• Published in: Journal of photochemistry and photobiology. B, Biology Vol. 172; pp. 77 - 87
• Main Authors: Fernández-Sainz, Jesús, Pacheco-Liñán, Pedro J., Granadino-Roldán, José M., Bravo, Iván, Garzón, Andrés, Rubio-Martínez, Jaime, Albaladejo, José
• Format: Journal Article
• Language: English
• Published: Switzerland Elsevier B.V 01.07.2017; Elsevier BV
• Subjects: Affinity; Albumin; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Apoptosis; Bi-2536; Binding Sites; Cancer; Docking; Drug-protein binding; Drugs; Entropy; Enzyme inhibitors; Fluorescence quenching; Human serum albumin; Humans; Inhibitor drugs; Ligand-protein docking; Molecular Docking Simulation; Pharmacodynamics; Pharmacology; Polo-like kinase; Protein Binding; Protein structure; Protein Structure, Secondary; Proteins; Pteridines - chemistry; Pteridines - metabolism; Quantum Theory; Secondary structure; Serum albumin; Serum Albumin - chemistry; Serum Albumin - metabolism; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Thermodynamics; Tissues; Tumor cell lines; Tumors; Human serum albumin; Drug-protein binding; Ligand-protein docking; Bi-2536; Fluorescence quenching
• ISSN: 1011-1344; 1873-2682
• DOI: 10.1016/j.jphotobiol.2017.05.016

BI-2536 is a potent Polo-like kinase inhibitor which induces apoptosis in diverse human cancer cell lines. The binding affinity of BI-2536 for human serum albumin (HSA) protein may define its pharmacokinetic and pharmacodynamic profile. We have studied the binding of BI-2536 to HSA by means of different spectroscopic techniques and docking calculations. We have experimentally observed that the affinity of BI-2536 for HSA is higher than that of other common HSA binding drugs. Therefore, it can be postulated that the drug dose should be increased to achieve a certain concentration of free drug in plasma, although BI-2536 could also reach tumour tissues by uptaking HSA/BI-2536 complex. Only a single binding site on HSA has been observed for BI-2536 which seems to correspond to the subdomain IIA pocket. The formation of the HSA/BI-2536 complex is a spontaneous and entropy-driven process that does not cause a significant change of the secondary structure of the protein. Its endothermic character could be related to proton release. Thermodynamic analysis showed that the main protein-drug interactions are of the van der Waals type although the presence of amide and ether groups in BI-2536 could also allow H-bonding with some residues in the subdomain IIA pocket. [Display omitted] •Determination of binding constant of the anticancer drug BI-2536 to HSA•Determination of thermodynamic parameters of the binding of BI-2536 with HSA•Theoretical docking study on the binding of BI-2536 with HSA