RESUMO
NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.
Assuntos
Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Ligantes , Linfócitos T CD8-Positivos , Ligação ProteicaRESUMO
Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medically and biologically important natural products characterized by structural and functional diversity. Advances in synthetic biology and semisynthetic methods may enable creation of an even more diverse set of non-natural product polyketides for drug discovery and other applications. However, the conformational sampling of these flexible compounds remains demanding. We developed and optimized a dihedral angle-based macrocycle conformational sampling method for macrocycles of arbitrary structure, and here we apply it to diverse polyketide natural products. First, we evaluated its performance using a data set of 37 polyketides with available crystal structures, with 9-22 rotatable bonds in the macrocyclic ring. Our optimized protocol was able to reproduce the crystal structure of polyketides' aglycone backbone within 0.50 Å RMSD for 31 out of 37 polyketides. Consistent with prior structural studies, our analysis suggests that polyketides tend to have multiple distinct low-energy structures, including the bioactive (target-bound) conformation as well as others of unknown significance. For this reason, we also introduce a strategy to improve both efficiency and accuracy of the conformational search by utilizing torsional restraints derived from NMR vicinal proton couplings to restrict the conformational search. Finally, as a first application of the method, we made blinded predictions of the passive membrane permeability of a diverse set of polyketides, based on their predicted structures in low- and high-dielectric media.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/metabolismo , Biologia Computacional/métodos , Policetídeos/química , Policetídeos/metabolismo , Bases de Dados de Proteínas , Modelos Moleculares , Conformação Molecular , PermeabilidadeRESUMO
Oxytocin (OT) is a peptide hormone agonist of the OT receptor (OTR) that plays an important role in social behaviors such as pair bonding, maternal bonding and trust. The pharmaceutical development of OT as an oral peptide therapeutic has been hindered historically by its unfavorable physicochemical properties, including molecular weight, polarity and number of hydrogen bond donors, which determines poor cell permeability. Here we describe the first systematic study of single and multiple N-methylations of OT and their effect on physicochemical properties as well as potency at the OT receptor. The agonist EC50 and percent effect for OTR are reported and show that most N-methylations are tolerated but with some loss in potency compared to OT. The effect of N-methylation on exposed polarity is assessed through the EPSA chromatographic method and the results validated against NMR temperature coefficient experiments and the determination of NMR solution structures. We found that backbone methylation of residues not involved in IMHB and removal of the N-terminal amine can significantly reduce the exposed polarity of peptides, and yet retain a significant OTR agonist activity. The results of this study also expose the potential challenge of using the N-methylation strategy for the OT system; while exposed polarity is reduced, in some cases backbone methylation produces a significant conformational change that compromises agonist activity. The data presented provides useful insights on the SAR of OT and suggests future design strategies that can be used to develop more permeable OTR agonists based on the OT framework.
Assuntos
Ocitocina/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Metilação , Relação Estrutura-Atividade , TemperaturaRESUMO
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.
Assuntos
Apetite , Receptor Tipo 4 de Melanocortina , Ratos , Humanos , Animais , Caquexia/tratamento farmacológico , Anorexia/tratamento farmacológico , Conformação MolecularRESUMO
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
RESUMO
Histidine triad nucleotide binding protein (HINT1) is an intracellular protein that binds purine mononucleotides. Strong sequence conservation suggests that these proteins play a fundamental role in cell biology, however its exact cellular function continues to remain elusive. nuclear magnetic resonance (NMR) studies using STD and HSQC were conducted to observe ligand binding to HINT1. These studies were confirmed using fluorescence spectroscopy titrations. We found that AICAR, the first non-phosphate containing ligand, binds to mouse histidine triad nucleotide binding protein 1 (HINT1). Chemical shift perturbations are mapped onto the X-ray structure showing AICAR binds at the same site as GMP. The NMR results demonstrated that this method will be valuable for the future screening of small molecules that can be used to modulate the function of HINT1.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Proteínas do Tecido Nervoso/química , Ribonucleosídeos/química , Aminoimidazol Carboxamida/química , Animais , Cristalografia por Raios X , Ligantes , Espectroscopia de Ressonância Magnética , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Espectrometria de FluorescênciaRESUMO
We have examined global chemical shift perturbations for aP2 ligand complexes and compared these with amide temperature coefficients. Hydrogen bond potential was monitored by amide chemical shift's temperature coefficient. Based on this information, we propose that the binding energy contribution can be spread out to multiple distant residues. For aP2, the ability of the receptor protein to change its hydrogen bond interactions in the beta-strands to accommodate different ligand scaffolds seems to make this receptor difficult for structure based drug design. While stabilization energy differential on hydrogen bonds is likely to be small for individual residues, the accumulative effect on multiple hydrogen bonds may have a dramatic impact on ligand affinity.
Assuntos
Proteínas de Ligação a Ácido Graxo/química , Ibuprofeno/química , Isomerismo , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Estrutura Terciária de Proteína , TemperaturaRESUMO
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
Assuntos
Peptídeos/química , Peptídeos/farmacologia , Peptoides/química , Peptoides/farmacologia , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Peptoides/administração & dosagem , Peptoides/farmacocinética , Ratos , Ratos WistarRESUMO
The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality.
RESUMO
Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.
Assuntos
Peptídeos/química , Conformação Proteica em alfa-Hélice , Safrol/análogos & derivados , Dicroísmo Circular , Modelos Moleculares , Oxirredução , Safrol/químicaRESUMO
As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.
RESUMO
Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.
Assuntos
Interleucina-17/antagonistas & inibidores , Interleucina-17/química , Peptídeos Cíclicos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Algoritmos , Sítios de Ligação , Células Cultivadas , Desenho de Fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Dinâmica Molecular , Peptídeos Cíclicos/química , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
A competitive low-affinity binding model was proposed for determining the number of mutual (overlapped) and specific binding sites of two ligands (A, B) on a protein (P). To use the model, one needs to carry out a titration experiment by adding either ligand A or B into a three-component system (A-B-P), and to monitor the spectroscopic parameter changes. Fitting the titration curve to the proposed model, one can get the mutual and specific binding sites of the two ligands on the protein. The model was examined by using human serum albumin (HSA) as a receptor and tolmetin (TOL) and salicylic acid (SAL) as ligands. Proton longitudinal relaxation rates (R1) were measured on a 500-MHz NMR spectrometer during the titration and used to derive the mutual binding sites. It was found that among the binding sites of 32+/-4 for SAL and 28+/-2 for TOL on HSA, there were 17+/-5 mutual sites for the two ligands. This result indicates that, although HSA has large binding capacities for most ligands, there are still a reasonable amount of the low-affinity binding sites that are structure selective.
Assuntos
Proteínas/química , Algoritmos , Sítios de Ligação , Ligação Competitiva/efeitos dos fármacos , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Químicos , Prótons , Ácido Salicílico/metabolismo , Soroalbumina Bovina/metabolismo , Tolmetino/metabolismoRESUMO
Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the ß-cells and hepatocytes. Since activation of glucokinase in ß-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.
Assuntos
Diabetes Mellitus Experimental/complicações , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Ácidos Nicotínicos/farmacologia , Animais , Ativadores de Enzimas/efeitos adversos , Ativadores de Enzimas/uso terapêutico , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Fígado/patologia , Masculino , Ácidos Nicotínicos/efeitos adversos , Ácidos Nicotínicos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Especificidade de Órgãos , RatosRESUMO
BACKGROUND: The effect of storage conditions on the microbiome and metabolite composition of human biological samples has not been thoroughly investigated as a potential source of bias. We evaluated the effect of two common storage conditions used in clinical trials on the bacterial and metabolite composition of the vaginal microbiota using pyrosequencing of barcoded 16S rRNA gene sequencing and (1)H-NMR analyses. METHODOLOGY/PRINCIPAL FINDINGS: Eight women were enrolled and four mid-vaginal swabs were collected by a physician from each woman. The samples were either processed immediately, stored at -80°C for 4 weeks or at -20°C for 1 week followed by transfer to -80°C for another 4 weeks prior to analysis. Statistical methods, including Kolmogorovo-Smirnov and Wilcoxon tests, were performed to evaluate the differences in vaginal bacterial community composition and metabolites between samples stored under different conditions. The results showed that there were no significant differences between samples processed immediately after collection or stored for varying durations. (1)H-NMR analysis of the small molecule metabolites in vaginal secretions indicated that high levels of lactic acid were associated with Lactobacillus-dominated communities. Relative abundance of lactic acid did not appear to correlate with relative abundance of individual Lactobacillus sp. in this limited sample, although lower levels of lactic acid were observed when L. gasseri was dominant, indicating differences in metabolic output of seemingly similar communities. CONCLUSIONS/SIGNIFICANCE: These findings benefit large-scale, field-based microbiome and metabolomic studies of the vaginal microbiota.
Assuntos
Bactérias/isolamento & purificação , Criopreservação , Vagina/metabolismo , Vagina/microbiologia , Esfregaço Vaginal , Adulto , Bactérias/genética , Criopreservação/métodos , Feminino , Humanos , Lactobacillus/genética , Lactobacillus/isolamento & purificação , Metagenoma , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , RNA Ribossômico 16S/genética , Esfregaço Vaginal/métodosRESUMO
Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.
Assuntos
Doença Celíaca/genética , Doença Celíaca/imunologia , Exposição Ambiental , Predisposição Genética para Doença , Glutens/efeitos adversos , Metaboloma/imunologia , Metagenoma/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoimunidade/imunologia , Bactérias/genética , Doença Celíaca/microbiologia , Fezes/microbiologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/patologia , Gliadina/imunologia , Antígenos HLA-DQ/imunologia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Espectroscopia de Ressonância Magnética , Filogenia , Análise de Componente Principal , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de RiscoRESUMO
Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analysis revealed the dynamics of five major classes of bacterial communities and showed that some communities change markedly over short time periods, whereas others are relatively stable. Modeling community stability using new quantitative measures indicates that deviation from stability correlates with time in the menstrual cycle, bacterial community composition, and sexual activity. The women studied are healthy; thus, it appears that neither variation in community composition per se nor higher levels of observed diversity (co-dominance) are necessarily indicative of dysbiosis.
Assuntos
Metagenoma/fisiologia , Vagina/microbiologia , Bactérias/classificação , Bactérias/genética , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Metaboloma , Metabolômica , Metagenoma/genética , Modelos Biológicos , Filogenia , Fatores de TempoRESUMO
HINT1 is a mouse histidine triad nucleotide binding protein. Here we report the assignments for the backbone nitrogen, carbon and proton NMR signals.
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Proteínas do Tecido Nervoso/química , Sequência de Aminoácidos , Animais , Isótopos de Carbono/química , Camundongos , Dados de Sequência Molecular , Isótopos de Nitrogênio/química , PrótonsRESUMO
The high-resolution (1)H NMR spectra as applied to Caco-2 cells during their differentiation into enterocyte like cells are presented. The data clearly reveal differences in the metabolic profiles over time as the Caco-2 cells differentiate. In the (1)H NMR spectra, the aliphatic regions from 4.5 to 1.0 ppm are dominated by peaks from myo-inositol, creatine, taurine, glutamine, glutamate, phosphatidylcholine, choline, alanine and lactate. While a majority of metabolites are present at both the early undifferentiated state and the late differentiated states, the levels of certain metabolites are seen to change dramatically, and in particular, the ratio of myo-inositol and taurine. The NMR spectrum from 10 to 5 ppm shows the aromatic amino acids (Phe, Tyr), NAD, ATP and ribose signals. The appearance of glucose resonances in the differentiated cells (30 days old) spectra suggests that these cells become gluconeogenic. Our study represents a novel method to analyze the differentiation of Caco-2 cells using a metabolomic approach. The results indicate, for the first time, that taurine and glucose biosynthesis occurs in these cells and thus by extension may occur in the intestine. This metabolomic approach can therefore be used to detect novel biological pathways as well as yield useful markers for differentiation.
Assuntos
Intestino Delgado/metabolismo , Metabolômica/métodos , Ressonância Magnética Nuclear Biomolecular/métodos , Células CACO-2 , Diferenciação Celular , Extratos Celulares , Glucose/metabolismo , Humanos , Metaboloma , Taurina/metabolismoRESUMO
Recent studies have suggested that ibuprofen inhibits low-density lipoprotein oxidation in a high dose-dependent manner and is a promising drug for treatment of the conditions associated with atherosclerosis. In this article, we present the NMR spectroscopic evidence for the interaction between ibuprofen and phospholipids in lipoprotein particles in intact human plasma. Ibuprofen caused chemical shift upfield drifts for the protons of -N(+)(CH(3))(3) moieties of phosphatidylcholine and sphingomyelin, olefinic chains (-CH[double bond]CH[bond], [bond]CH[triple bond]CHCH(2)CH[triple bond]CH[bond], [bond](CH(2))(n)CH(2)CH[double bond]), and (CH(2))(n) and CH(3) groups, from unsaturated lipids in lipoprotein particles. The ibuprofen may interact directly with the above-mentioned groups of phospholipids or induce structural changes in the lipoproteins. This may shed light on the mechanism by which the drug protects against oxidative modification of lipoproteins.