Zusammenfassung
The binding of the nonsteroidal anti-inflammatory drug ibuprofen (IBU)
to human serum albumin (HSA) is investigated using density functional
theory (DFT) calculations within a fragmentation strategy.
Crystallographic data for the IBU-HSA supramolecular complex shows that
the ligand is confined to a large cavity at the subdomain IIIA and at
the interface between the subdomains IIA and IIB, whose binding sites
are FA3/FA4 and FA6, respectively. The interaction energy between the
IBU molecule and each amino acid residue of these HSA binding pockets
was calculated using the Molecular Fractionation with Conjugate Caps
(MFCC) approach employing a dispersion corrected exchange-correlation
functional. Our investigation shows that the total interaction energy of
IBU bound to HSA at binding sites of the fatty acids FA3/FA4 (FA6)
converges only for a pocket radius of at least 8.5 angstrom, mainly due
to the action of residues Arg410, Lys414 and Ser489 (Lys351, Ser480 and
Leu481) and residues in nonhydrophobic domains, namely Ile388, Phe395,
Phe403, Leu407, Leu430, Val433, and Leu453 (Phe206, Ala210, Ala213, and
Leu327), which is unusual. Our simulations are valuable for a better
understanding of the binding mechanism of IBU to albumin and can lead to
the rational design and the development of novel IBU-derived drugs with
improved potency.
Nutzer