1,720,982 research outputs found
Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. A comprehensive systematic review
No full textSmall molecule inhibitors of adipocyte fatty acid binding protein 4 (FABP4) have attracted interest following the recent publications of beneficial pharmacological effects of these compounds. FABP4 is predominantly expressed in macrophages and adipose tissue where it regulates fatty acids (FAs) storage and lipolysis and is an important mediator of inflammation. In the past years, hundreds FABP4 inhibitors have been synthesized for effective atherosclerosis and diabetes treatments, including derivatives of niacin, quinoxaline, aryl-quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds. This review provides an overview of the synthesized and discovered molecules as adipocyte fatty acid binding protein 4 inhibitors (FABP4is) since the synthesis of the putative FABP4i, BMS309403, highlighting the interactions of the different classes of inhibitors with the targets
Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis
No full textFor the first time in sigma-2 (σ2) receptor field, a quantitative structure–activity relationship (QSAR) model has been built using pKi values of the whole set of known selective σ2 receptor ligands (548 compounds), taken from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) (http://www.researchdsf.unict.it/S2RSLDB/), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (σ2 receptor pKi). The statistical quality reached, suggested that model for pKi determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as σ2 receptor ligands (predicted pKi ≥ 8). A literature check showed that six of these compounds have already been tested for affinity at σ2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental σ2 receptor pKi > 7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the σ2 receptor, and overall allowing for an enhanced hit rate respect to a random screening
Synthesis and evaluation of haloperidol metabolite II prodrugs as anticancer agents
No full textThe use of haloperidol metabolite II (HP-metabolite II) prodrugs is an emerging strategy in the treatment of cancer. HP-metabolite II exhibits antiproliferative properties at micromolar concentrations inducing apoptosis in different types of cancer. Thus, the application of the prodrug approach appears as a useful method leading to much more desirable pharmacokinetic and pharmacodynamic properties. Some studies have shown that the esterification of the hydroxyl group of HP-metabolite II with 4-phenylbutiric acid (4-PBA) or valproic acid enhances the anticancer therapeutic potency. The current progresses in the design, synthesis and evaluation of anticancer activity of HP metabolite II prodrugs will be discussed in this review
Hyphenated 3D-QSAR statistical model-scaffold hopping analysis for the identification of potentially potent and selective sigma-2 receptor ligands
No full textA 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the Ï 2receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel Ï 2receptor ligands. The model has been built using a set of 500 selective Ï 2receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn up 3D map allows for a prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying Ï 2receptor ligands interaction. A theoretic approach for the generation of new lead compounds with optimized Ï 2receptor affinity has been performed by means of scaffold hopping analysis. Obtained results further confirmed the validity of our model being some of the identified moieties have already been successfully employed in the development of potent Ï 2receptor ligands. For the first time is herein reported a 3D-QSAR model which includes a number of chemically diverse Ï 2receptor ligands and well accounts for the individual ligands affinities. These features will ensure prospectively advantageous applications to speed up the identification of new potent and selective Ï 2receptor ligands
Recent advances in drug discovery of phototherapeutic non-porphyrinic anticancer agents
No full textIn the search of novel strategies for the treatment of cancer, photodynamic therapy (PDT) has emerged as an effective, safe for repeated use, and non-invasive method. This technique involves the use of two major non-toxic components, a photosensitizer (PS) and a visible or near-infrared (NIR) light source, combined to induce cellular damage in an oxygen-dependent or -independent manner. Macrocyclic compounds, involving porphyrin and their derivatives, represent the major class of PS agents used in PDT. However, due to the drawbacks associated with these PS, like photosensitivity, dark toxicity, and low wavelength absorbance, new classes of PS appear to be needed. This review summarizes over the recent advances in drug discovery of non-porphyrinic PS suitable as anticancer therapeutics in PDT. The different compounds are grouped by chemical classes and discussed in terms of phototoxicity, together with the critical aspects of design and structure-activity relationship
Novel Sigma-1 receptor antagonists: From opioids to small molecules: What is new?
No full textSigma-1 (Ï 1) receptor has been identified as a chaperone protein that interacts with other proteins, such as N-methyl-D-aspartate (NMDA) and opioid receptors, modulating their activity. Ï 1receptor antagonists have been developed to obtain useful compounds for the treatment of psychoses, pain, drug abuse and cancer. Some interesting compounds such as E-5842 (5) and MS-377 (24), haloperidol and piperazine derivatives, respectively, were endowed with high affinity for Ï 1receptors (KiÏ 1= 4 and 73 nM; KiÏ 2= 220 and 6900, respectively). They were developed for the treatment of psychotic disorders and 5 also underwent Phase II clinical trials suggesting interesting potential therapeutic applications. Here, Ï 1receptor antagonists have been grouped based on chemical structure and reviewed according to structure-activity relationship and potential therapeutic role
Sigma-2 receptor ligands QSAR model dataset
Full text linkThe data have been obtained from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) and refined according to the QSAR requirements. These data provide information about a set of 548 Sigma-2 (σ2) receptor ligands selective over Sigma-1 (σ1) receptor. The development of the QSAR model has been undertaken with the use of CORAL software using SMILES, molecular graphs and hybrid descriptors (SMILES and graph together). Data here reported include the regression for σ2 receptor pKi QSAR models. The QSAR model was also employed to predict the σ2 receptor pKi values of the FDA approved drugs that are herewith included
Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase
No full textIn this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5ʹ-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5ʹ-monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME-Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood–brain barrier, and is non-carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5ʹ-monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C–C bond cleavage
Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D-QSAR Coupled to Scaffold-Hopping Analysis
No full textA 3D quantitative structure–activity relationship (3D-QSAR) model for predicting the activity of heme oxygenase 1 (HO-1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO-1 inhibitors. The model was built using a set of 222 HO-1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn-up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO-1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold-hopping analysis. For the first time, a 3D-QSAR model is reported for this target, and was built with a number of chemically diverse HO-1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO-1. These features will ensure application in accelerating the identification of new potent and selective HO-1 inhibitors
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