Stereoselectivity of Interaction of Nonsteroidal Anti-Inflammatory Drug S-Ketoprofen with L/D-Tryptophan in Phospholipid Membranes

Abstract

The mechanisms of stereoselectivity of the interaction of chiral drugs with active sites of enzymes and cell receptors attract significant attention. The first reason is the difference in therapeutic activity of the enantiomers of the common drugs. Another reason is the interest in the role of chiral inversion of amino acids involved in various peptides in the development of many diseases including Alzheimer’s, Parkinson’s, type II diabetes, and a number of other pathological conditions. In our study we use elementary chemical process—electron transfer (ET) to simulate individual stages of ligand–receptor and enzyme–substrate interactions. In particular, previous studies of photoinduced ET in chiral donor-acceptor dyads consisting of the nonsteroidal anti-inflammatory drug (R/S)-ketoprofen and (L)-tryptophan show the stereo and spin selectivity of ET in diastereomers. The present study is devoted to the interaction of (S)-ketoprofen with L- and D-enantiomers of tryptophan in homogeneous aqueous solution and in phospholipid membranes. The study was done using the NMR technique and molecular modeling. These approaches confirm efficient penetration of ketoprofen into the lipid bilayer and binding with tryptophan molecule. The short-lived paramagnetic intermediates formed during the photoinduced ET from electron donor tryptophan to ketoprofen have been detected using the chemically induced dynamic nuclear polarization (CIDNP) technique. It was found that S-ketoprofen interacts stereoselectively with tryptophan enantiomers in the lipid membrane. The formation of the ketyl radical of ketoprofen under irradiation leads to the oxidation of membrane lipids and may be the cause of ketoprofen phototoxicity. However, in contrast to a homogeneous solution in phosphate buffer saline, where the amino acid tryptophan accelerates the photodecomposition of KP due to intramolecular hydrogen transfer, tryptophan in a lipid membrane significantly reduces the rate of photodegradation due to a reversible electron (or hydrogen) transfer reaction. The stereoselectivity in the rate of KP and lipids decomposition under UV irradiation of S-ketoprofen in the presence of tryptophan enantiomers in lipid bilayer has been detected.

Keywords

• ketoprofen
• L-tryptophan
• D-tryptophan
• lipid membranes
• electron transfer
• stereoselectivity