Protein Binding of Lapatinib and Its N- and O-Dealkylated Metabolites Interrogated by Fluorescence, Ultrafast Spectroscopy and Molecular Dynamics Simulations

Switching from ultrafast electron transfer to proton transfer in excited drug–protein complexes upon biotransformation

“…Previous studies on the photobehavior of LAP and its metabolites by means of spectroscopic techniques have shown that their photophysical properties are strongly mediumdependent. 16,17 A similar result was recently obtained for the parent drug GFT. 12 Thus, excitation of these anticancer drugs in organic non-polar solvents or in biological media leads to the formation of locally excited (LE) singlet states.…”

“… 48 HSA employs three main binding sites for recognition: site 1 (subdomain IIA), site 2 (subdomain IIIA) and site 3 (subdomain IB). Based on the structural similarity of the basic core of GFT ( N -phenylquinazolin-4-amine moiety) with lapatinib, which was reported to bind to site 3, 17 this region was selected for docking. The protein coordinates found in the crystal structure of HSA in complex with hemin (PDB entry ), 22 which also binds to subdomain IB, was used for these studies.…”

“…The protocol was performed as described for LAP, N-LAP and O-LAP in HSA. 17 The cpptraj module in AMBER 17 was Please do not adjust margins Please do not adjust margins used to analyze the trajectories and to calculate the rmsd of the protein and the ligand during the simulation. 23 The molecular graphics program PyMOL 24 was employed for visualization and depicting enzyme structures.…”

Photoprocesses of the tyrosine kinase inhibitor gefitinib: from femtoseconds to microseconds and from solution to cells

“…17 The excited states arising from irradiation of LAP with UV light have been investigated by means of spectroscopic techniques in solution and in the presence of human serum albumin (HSA). 18,19 It has been shown that short-lived (ps scale) intramolecular charge transfer states (ICT) are formed in the bulk solution, while longer-lived locally excited (LE) states predominate in the protein-bound LAP; these states must be related with the photosensitizing potential of the drug.…”

Intrinsically Fluorescent Anti-Cancer Drugs

“…An important aspect was the complementation of the experimental results with simulation studies. In another study the same group [ 62 ] examined the interaction of Lapitinib and its metabolites with serum proteins. The fluorescence results pointed to a higher affinity of Lapatinib and its metabolites to human proteins (human serum albumin (HSA)) in comparison to bovine proteins; the highest affinity complex was found for Lapatinib-HSA.…”