Quantum molecular modelling of ibuprofen bound to human serum albumin

Abstract

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 8.5Å, 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.

Studies of intermolecular interactions in solid dispersions using advanced surface chemical analysis

“…It has been seen that very few molecular studies in the literature have reported on MD-based molecular modelling to describe solid dispersion process as well as drug-polymer interactions. [7][8][9][10][11][12][13][14][15][16] Recently, the quantum mechanical (QM) calculations (Gaussian 09) were used to identify drug/polymer interactions.…”

Applicability of capillary electrophoresis‐frontal analysis for displacement studies: Effect of several drugs on l‐tryptophan and lidocaine binding to human serum albumin

“…According to information in the literature, DCF binds to Site I with high affinity and Site II with low affinity [40,41]. IBU binds mainly to Site II with high affinity, but some articles also describe its binding to a fatty acid binding site located at the interface between the IIA and IIB domains [42,43]. Several articles describe the binding of CP to Site I [38,44], but in a study by Tao et al a secondary binding site in subdomain IIIA (Site II) was also observed [45].…”

Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry

“… 50 and Dantas et al . 51 to calculate binding affinity in protein-ligand complexes, by assuming different values of the dielectric constant ( ε ) to take into account the effect of the protein and solvent environment in the evaluation of the electrostatic energies. Here, we have employed the MFCC approach together with the CPCM (Conductor-like Polarizable Continuum Model) continuum solvation model 52 with dielectric constants ε considered to be 20 ( ε 20 and 40 ( ε 40 ), respectively) to increase the similarity with the protein environment and estimate energy effects, such as the electrostatic polarization promoted by the solvent.…”