Structural investigations of stereoselective profen binding by equine and leporine serum albumins

Abstract

Serum albumin, the most abundant transport protein of mammalian blood, interacts with various nonsteroidal anti‐inflammatory drugs (NSAIDs) affecting their disposition, metabolism, and excretion. A big group of chiral NSAIDs transported by albumin, profens, is created by derivatives of 2‐arylpropionic acid. The chiral center in the structures of profens is adjacent to the carboxylate moiety and often determines different pharmacological properties of profen enantiomers. This study describes crystal structures of two albumins, isolated from equine and leporine serum, in complexes with three profens: ibuprofen, ketoprofen, and suprofen. Based on three‐dimensional structures, the stereoselectivity of albumin is discussed and referred to the previously published albumin complexes with drugs. Drug Site 2 (DS2) of albumin, the bulky hydrophobic pocket of subdomain IIIA with a patch of polar residues, preferentially binds (S)‐enantiomers of all investigated profens. Almost identical binding mode of all these drugs clearly indicates the stereoselectivity of DS2 towards (S)‐profens in different albumin species. Also, the affinity studies show that DS2 is the major site that presents high affinity towards investigated drugs. Additionally, crystallographic data reveal the secondary binding sites of ketoprofen in leporine serum albumin and ibuprofen in equine serum albumin, both overlapping with previously identified naproxen binding sites: the cleft formed between subdomains IIIA and IIIB close to the fatty acid binding site 5 and the niche created between subdomains IIA and IIIA, called fatty acid site 6.

Albumin–Hyaluronan Interactions: Influence of Ionic Composition Probed by Molecular Dynamics

“…On the other hand, IIIA and IIIB are involved in all 12 assemblies determined through the docking procedure as best fitted complexes for the given docking algorithm. Interestingly, both fragments and in some cases IB are involved in the binding of non-steroidal molecules containing carboxylic groups, such as ibuprofen, ketoprofen, naproxen, diclofenac, and indomethacin [42][43][44]. Furthermore, it seems to be quite probable that the S configuration of hyaluronate carboxylic acid groups is beneficial for binding with the IIIA and IIIB subdomains, since (S)-enantiomers of 2-arylpropionic acids are capable of forming more stable interactions than (R)-enantiomers [42].…”

“…Interestingly, both fragments and in some cases IB are involved in the binding of non-steroidal molecules containing carboxylic groups, such as ibuprofen, ketoprofen, naproxen, diclofenac, and indomethacin [42][43][44]. Furthermore, it seems to be quite probable that the S configuration of hyaluronate carboxylic acid groups is beneficial for binding with the IIIA and IIIB subdomains, since (S)-enantiomers of 2-arylpropionic acids are capable of forming more stable interactions than (R)-enantiomers [42]. However, we note that the higher hydrophilicity of HA suggests a different nature of the binding of HA and acrylpropionic acid to albumin.…”

Enantioresolution and Binding Affinity Studies on Human Serum Albumin: Recent Applications and Trends

“…A recent example described that for some profens, such as etodolac, indoprofen, ibuprofen, and ketoprofen, the plasma protein bond was strongest for the (R)-enantiomer. Additionally, it was found that the different interaction that occurs between plasma proteins with the profen enantiomers influenced the metabolic behavior and drug interactions [31]. Other recent examples concern the stereoselective binding of cytosine nucleoside enantiomers [32], lactic acid [33] and ginsenoside Rh2 [34] to human serum albumin (HSA).…”

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

“…There are many studies concerning enantioselective binding to HSA [ 23 ]. For example, there are drugs such as profens, where the HSA bond is strongest for the ( R ) enantiomer, such as etodolac, indoprofen, ibuprofen, and ketoprofen [ 25 ]. It was observed that the different interaction that occurs between HSA with ( R )- and ( S )-profens influences metabolic behavior and drug interactions [ 25 ].…”

“…For example, there are drugs such as profens, where the HSA bond is strongest for the ( R ) enantiomer, such as etodolac, indoprofen, ibuprofen, and ketoprofen [ 25 ]. It was observed that the different interaction that occurs between HSA with ( R )- and ( S )-profens influences metabolic behavior and drug interactions [ 25 ]. The preferable interactions of the ( R )-enantiomer of ibuprofen with HSA causes a greater proportion of the ( S )-enantiomer in free form.…”