164 research outputs found

    Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease

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    Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl hydrazone (5a–l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood–brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents

    In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development

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    The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as “multi-target-directed ligands” (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development. In this study more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment: acetylcholinesterase (AChE), histone deacetylase 2 (HDAC2), and monoamine oxidase B (MAO-B). The compounds with affinities below 5.0 µM for all studied targets were additionally filtered to remove known non-specifically binding or unstable compounds. The selected four hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs

    New Potential Pharmacological Targets of Plant-Derived Hydroxyanthraquinones from Rubia spp.

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    The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from Rubia cordifolia spp., as similar to gatifloxacin, a synthetic antibacterial agent. This suggested the bacterial DNA gyrase and DNA topoisomerase IV as potential pharmacological targets of pseudopurpurin. In this study, estimation of structural similarity to referent antibacterial agents and molecular docking in the DNA gyrase and DNA topoisomerase IV complexes were performed for a homologous series of four hydroxyanthraquinones. Estimation of shape- and chemical feature-based similarity with (S)-gatifloxacin, a DNA gyrase inhibitor, and (S)-levofloxacin, a DNA topoisomerase IV inhibitor, outlined pseudopurpurin and munjistin as the most similar structures. The docking simulations supported the hypothesis for a plausible antibacterial activity of hydroxyanthraquinones. The predicted docking poses were grouped into 13 binding modes based on spatial similarities in the active site. The simultaneous presence of 1-OH and 3-COOH substituents in the anthraquinone scaffold were emphasized as relevant features for the binding modes’ variability and ability of the compounds to strongly bind in the DNA-enzyme complexes. The results reveal new potential pharmacological targets of the studied polyphenols and help in their prioritization as drug candidates and dietary supplements

    A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors

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    Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings

    Application of InterCriteria Analysis to Assess the Performance of Scoring Functions in Molecular Docking Software Packages

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    (1) Background: In silico approaches to rational drug design are among the fastest evolving ones. Depending on the available structural information for the biomacromolecule and the small molecule, the in silico methods are classified as ligand- and structure-based. The latter predict ligand–receptor binding using 3D structures of both molecules, whose computational simulation is referred to as molecular docking. It aims at estimating the binding affinity (approximated by scoring function) and the ligand binding pose in the receptor’s active site, which postulates a key role of the scoring functions in molecular docking algorithms. This study focuses on the performance of different types of scoring functions implemented in molecular modelling software packages. (2) Methods: An InterCriteria analysis (ICrA) was applied to assess the performance of the scoring functions available in MOE, GOLD, SeeSAR, and AutoDock Vina software platforms. The InterCriteria analysis was developed to distinguish possible relations between pairs of criteria when multiple objects are considered. All 12 investigated scoring functions were tested by docking a set of protease inhibitors in the binding sites of two protein targets. The dataset consisted of 88 benzamidine-type compounds with experimentally measured inhibitory constants for thrombin and trypsin, which allows for the objective assessment of the scoring functions performance. The results generated by the molecular docking were subjected to ICrA in order to analyze both docking energies as approximations of the binding affinities and RMSDs (root-mean-square deviation) as measures of the experimental binding pose proximity between the compounds and the co-crystalized ligand, based on the atoms in the common scaffold. (3) Results: The results obtained for the best poses, the average of the best 5 or 30 poses retained after docking, were analyzed. A comparison with the experimentally observed inhibitory effects was also performed. The InterCriteria analysis application confirms that the performance of the scoring functions for the same dataset of ligands depends on the studied protein. The analysis reveals that none of the studied scoring functions is a good predictor of the compounds’ binding affinities for the considered protein targets. (4) Conclusion: In terms of this analysis, the investigated scoring functions do not produce equivalent results, which suggests the necessity for their combined use in consensus docking studies

    The crystal structure of (4SR)-7-(3,4-dichlorobenzyl)-4,8,8-trimethyl-7,8-dihydroimidazo[5,1c][1, 2,4]triazine-3,6(2H,4H)-dione, C15H16Cl2N4O2

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    Tzvetkov NT, Peeva MI, Tsakovska I, Milella L, Pajeva I, Stammler H-G. The crystal structure of (4SR)-7-(3,4-dichlorobenzyl)-4,8,8-trimethyl-7,8-dihydroimidazo[5,1c][1, 2,4]triazine-3,6(2H,4H)-dione, C15H16Cl2N4O2. Zeitschrift fĂĽr Kristallographie - New Crystal Structures . 2022.C15H16Cl2N4O2, monoclinic, P2(1)/c (no. 14), a = 26.2014(7) angstrom, b = 7.59320(10) angstrom, c = 17.9766(4) angstrom, beta = 109.217(3)degrees, V = 3377.20(14) angstrom(3), Z = 8, R ( gt )(F) = 0.0503, wR ( ref )(F (2)) = 0.1411, T = 100.0(1) K

    Hybrid Classification/Regression Approach to QSAR Modeling of Stoichiometric Antiradical Capacity Assays’ Endpoints

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    Quantitative structure–activity relationships (QSAR) are a widely used methodology allowing not only a better understanding of the mechanisms of chemical reactions, including radical scavenging, but also to predict the relevant properties of chemical compounds without their synthesis, isolation and experimental testing. Unlike the QSAR modeling of the kinetic antioxidant assays, modeling of the assays with stoichiometric endpoints depends strongly on the number of hydroxyl groups in the antioxidant molecule, as well as on some integral molecular descriptors characterizing the proportion of OH-groups able to enter and complete the radical scavenging reaction. In this work, we tested the feasibility of a “hybrid” classification/regression approach, consisting of explicit classification of individual OH-groups as involved in radical scavenging reactions, and using further the number of these OH-groups as a descriptor in simple-regression QSAR models of antiradical capacity assays with stoichiometric endpoints. A simple threshold classification based on the sum of trolox-equivalent antiradical capacity values was used, selecting OH-groups with specific radical stability- and reactivity-related electronic parameters or their combination as “active” or “inactive”. We showed that this classification/regression modeling approach provides a substantial improvement of the simple-regression QSAR models over those built on the number of total phenolic OH-groups only, and yields a statistical performance similar to that of the best reported multiple-regression QSARs for antiradical capacity assays with stoichiometric endpoints

    Computational Analysis of Chemical Space of Natural Compounds Interacting with Sulfotransferases

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    International audienceThe aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes

    Cytotoxicity and Microbicidal Activity of Commonly Used Organic Solvents: A Comparative Study and Application to a Standardized Extract from Vaccinium macrocarpon

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    The cytotoxicity and microbicidal capacity of seven organic solvents commonly applied for studying plant extracts and bioactive compounds were systematically investigated based on international standards. Four cell lines of normal (CCL-1, HaCaT) or tumor (A-375, A-431) tissue origin, seven bacterial and one fungal strain were used. The impact of the least toxic solvents in the determination of in vitro cytotoxicity was evaluated using a standardized extract from Vaccinium macrocarpon containing 54.2% v/v proanthocyanidins (CystiCran®). The solvents ethanol, methoxyethanol and polyethylene glycol were the least cytotoxic to all cell lines, with a maximum tolerated concentration (MTC) between 1 and 2% v/v. Ethanol, methanol and polyethylene glycol were mostly suitable for antimicrobial susceptibility testing, with minimum inhibitory concentrations (MICs) ≥ 25% v/v. The MTC values of the solvents dimethyl sulfoxide, dimethoxyethane and dimethylformamide varied from 0.03% to 1.09% v/v. The MICs of dimethyl sulfoxide, methoxyethanol and dimethoxyethane were in the range of 3.125–25% v/v. The cytotoxic effects of CystiCran® on eukaryotic cell lines were directly proportional to the superimposed effect of the solvents used. The results of this study can be useful for selecting the appropriate solvents for in vitro estimation of the cytotoxic and growth inhibitory effects of bioactive molecules in eukaryotic and prokaryotic cells
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