Small Molecule Inhibitors of Human Adipocyte Fatty Acid Binding Protein (FABP4)

Zhang, Mingming; Zhu, Weiliang; Li, Yingxia

doi:10.2174/15734064113096660045

Cited by 13 publications

(6 citation statements)

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“…Bile acid-conjugated gadolinium chelates devised as hepatospecific contrast agents in magnetic resonance imaging (MRI) have been demonstrated to actually bind to c-FABPL [ 48 , 49 ]. As involved in cytokine production and cholesterol metabolism, FABPAs are connected with inflammatory and metabolic disorders [ 50 ]; compounds with high affinity for FABPAs and high selectivity against all other FABPs thus have the potential to prevent or treat diseases such as type-2 diabetes and atherosclerosis [ 51 – 53 ].…”

Section: Discussionmentioning

confidence: 99%

All-Purpose Containers? Lipid-Binding Protein – Drug Interactions

et al. 2015

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The combined use of in vitro (19F-NMR) and in silico (molecular docking) procedures demonstrates the affinity of a number of human calycins (lipid-binding proteins from ileum, liver, heart, adipose tissue and epidermis, and retinol-binding protein from intestine) for different drugs (mainly steroids and vastatins). Comparative evaluations on the complexes outline some of the features relevant for interaction (non-polar character of the drugs; amino acids and water molecules in the protein calyx most often involved in binding). Dissociation constants (Ki) for drugs typically lie in the same range as Ki for natural ligands; in most instances (different proteins and docking conditions), vastatins are the strongest interactors, with atorvastatin ranking top in half of the cases. The affinity of some calycins for some of the vastatins is in the order of magnitude of the drug Cmax after systemic administration in humans. The possible biological implications of this feature are discussed in connection with drug delivery parameters (route of administration, binding to carrier proteins, distribution to, and accumulation in, human tissues).

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Section: Discussionmentioning

confidence: 99%

All-Purpose Containers? Lipid-Binding Protein – Drug Interactions

et al. 2015

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“…Genetic deletion, either constitutive or through silencing approaches, has shown remarkable consistency in the improvement of metabolic phenotypes in multiple independent studies (5, 6, 8, 14, 15, 33). These studies have been complemented with small-molecule inhibitors, particularly BMS309403, but also with more potent related small molecules (49), which inhibit lipid binding and reduce the activity of FABP4 both intracellularly and presumably in circulation (40). These aspects require further clarification.…”

Section: Therapeutic Targeting Of Fabp4mentioning

confidence: 99%

Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses

Prentice

Saksi

Hotamışlıgil

2019

Journal of Lipid Research

120

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Although counterregulatory hormones and mediators of the fight-or-flight responses are well defined at many levels, how energy stores per se are integrated into this system remains an enigmatic question. Recent years have seen the adipose tissue become a central focus for mediating intracellular signaling and communication through the release of a variety of bioactive lipids and substrates, as well as various adipokines. A critical integration node among these mediators and responses is controlled by FA binding protein 4 (FABP4), also known as adipocyte protein 2 (aP2), which is highly expressed in adipose tissue and functions as a lipid chaperone protein. Recently, it was demonstrated that FABP4 is a secreted hormone that has roles in maintaining glucose homeostasis, representing a key juncture facilitating communication between energy-storage systems and distant organs to respond to life-threatening situations. However, chronic engagement of FABP4 under conditions of immunometabolic stress, such as obesity, exacerbates a number of immunometabolic diseases, including diabetes, asthma, cancer, and atherosclerosis. In both preclinical mouse models and humans, levels of circulating FABP4 have been correlated with metabolic disease incidence, and reducing FABP4 levels or activity is associated with improved metabolic health. In this review, we will discuss the intriguing emerging biology of this protein, including potential therapeutic options for targeting circulating FABP4.

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“…Fatty acid binding protein 4 is a protein involved in fatty acid transport, and as such, represents a drug target for the treatment of obesity (Schlottmann et al, 2014;Zhang et al, 2014). So far, only ligands that bind to the active site and directly compete with the binding of fatty acids are known.…”

Section: Direct Competition Of Fabp4 Ligandsmentioning

confidence: 99%

Elucidation of direct competition and allosteric modulation of small-molecular-weight protein ligands using surface plasmon resonance methods

et al. 2015

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The present work introduces a surface plasmon resonance-based method for the discrimination of direct competition and allosteric effects that occur in ternary systems comprising a receptor protein and two small-molecular-weight ligands that bind to it. Fatty acid binding protein 4, fructose-1,6-bisphosphatase and human serum albumin were used as model receptor molecules to demonstrate the performance of the method. For each of the receptor molecules, pairs of ligand molecules were selected for which either direct competition or an allosteric effect had already been determined by other methods. The method of discrimination introduced here is based on the surface plasmon resonance responses observed at equilibrium when an immobilized receptor protein is brought into contact with binary mixtures of interacting ligands. These experimentally determined responses are compared with the responses calculated using a theoretical model that considers both direct competition and allosteric ligand interaction modes. This study demonstrates that the allosteric ternary complex model, which enables calculation of the fractional occupancy of the protein by each ligand in such ternary systems, is well suited for the theoretical calculation of these types of responses. For all of the ternary systems considered in this work, the experimental and calculated responses in the chosen concentration ratio range were identical within a five-σ confidence interval when the calculations considered the correct interaction mode of the ligands (direct competition or different types of allosteric regulation), and in case of allosteric modulation, also the correct strength of this effect. This study also demonstrates that the allosteric ternary complex model-based calculations are well suited to predict the ideal concentration ratio range or even single concentration ratios that can serve as hot spots for discrimination, and such hot spots can drastically reduce the numbers of measurements needed for discrimination between direct competition and distinct modulation modes (neutral, positive or negative allostery).

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Small Molecule Inhibitors of Human Adipocyte Fatty Acid Binding Protein (FABP4)

Cited by 13 publications

References 0 publications

All-Purpose Containers? Lipid-Binding Protein – Drug Interactions

All-Purpose Containers? Lipid-Binding Protein – Drug Interactions

Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses

Elucidation of direct competition and allosteric modulation of small-molecular-weight protein ligands using surface plasmon resonance methods

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