Chiral recognition of 2-(3-benzoylphenyl)propionic acid (ketoprofen) by serum albumin: an investigation with microcalorimetry, circular dichroism and molecular modelling

Abstract

The interaction of enantiomeric ketoprofen (KP) with BSA and HSA was studied by isothermal titration calorimetry (ITC). Affinity constants and thermodynamic parameters for complexation in two main protein sites were determined. Affinity constants for both proteins are generally lower for S(+)- than for R(-)-KP. Large enthalpic contributions to Gibbs free energy are compensated by large negative entropic terms for S(+) in the BSA-subdomain IIIA and HSA-subdomain IIA. The lowest energy BSA complexes of both enantiomers were structurally characterized by combining molecular mechanics (MM) and molecular dynamics (MD) with circular dichroism (CD). Comparison of quantum mechanically calculated rotational strengths with the CD signals of the complexes supported the structures. These allowed to identify the main interactions of the KP enantiomers with surrounding amino acids at short distances, that limit significantly KP mobility in both sites. In the primary binding site S(+) is close to Tyr 409 in subdomain IIIA (Sudlow site II), and R(-) is close to Trp 212 and His 240 in subdomain IIA (Sudlow site I). The same sites are involved in the formation of 2:1 complexes. The equilibrium structures are characterized by marked geometrical distortion of KP.

Stereoselective binding of chiral drugs to plasma proteins

“…In the last decade, several models have been developed to study the binding between HSA and restricted drug families 45,46,47 , and a few global models have been developed based on different approaches, such as genetic function approximation, multiple linear regression, heuristic regression procedures and ant colony systems 48,49,50 . Monti et al combined molecular mechanisms (MM) and molecular dynamics (MD) with circular dichroism (CD) to identify the main interactions between ketoprofen enantiomers and the surrounding amino acids at short distances in bovine serum albumin 51 . Similarly, Yu et al took advantage of MM and MD to identify several key residues that are involved in the enantioselectivity for the binding of AGP to mexiletine enantiomers, such as Arg90 43 .…”

Interaction of bovine serum albumin with starch nanoparticles prepared by TEMPO-mediated oxidation

“…The results showed that K SV values varied according to temperature, with K SV values decreasing as the temperature increased. As we know, dynamic quenching depends on diffusion, and the coefficient of diffusion will augment with the increase of temperature [41]. However, for static quenching, the stability of complex formations will decrease with the increase of temperature, so the quenching constant is inversely correlated with temperature [27].…”

Thermodynamic investigations of ligand–protein interactions: Binding of the phenazinium dyes phenosafranin and safranin O with human serum albumin

“…Many small molecules like drugs, dyes etc. bind to cellular serum proteins to exert their adverse and normal functions and a large number of studies have been recently undertaken in this direction [1][2][3][4][5][6][7][8][9][10][11][12]. Small dye molecules can be potentially dangerous to our environment and many living objects due to toxic, carcinogenic and polluting properties, nevertheless they are being widely used in our day today life.…”