Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Poli, Giulio; Dimmito, Marilisa Pia; Mollica, Adriano; Zengin, Gökhan; Benyhe, Sándor; Zádor, Ferenc; Stefanucci, Azzurra

doi:10.3390/molecules24213872

Cited by 20 publications

(13 citation statements)

References 40 publications

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“…On the other hand, both Goldscore and Chemscore were able to find a similar pose of tropolone superimposable to the crystallographic one with similar RMSD in the range of 2-3 angstorms. The best RMSD value self-docking of tropolone was obtained by using the Chemscore methods (RMSD = 2.33 Å), which was considerate good following the data reported in other works e.g., References [55,56]. The self docking also revealed that the best pose is similar to the crystallographic pose of tropolone cocrystallized to the tyrosinase-like 1 enzyme [57].…”

Section: Adme Estimationsupporting

confidence: 80%

Phenolic Profile, Toxicity, Enzyme Inhibition, In Silico Studies, and Antioxidant Properties of Cakile maritima Scop. (Brassicaceae) from Southern Portugal

Placines

Castañeda-Loaiza

Rodrigues

et al. 2020

Plants

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Cakile maritima Scop. (sea rocket) is an edible halophyte plant with several ethnomedicinal uses. This work reports the chemical profile and bioactivities of food grade extracts from sea rocket organs. Toxicity was determined on mammalian cells, and phenolic profiling and the quantitation of the main metabolites were made by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Enzymatic inhibition was determined towards acetyl- and butyrylcholinesterase (AChE, BuChE), α-glucosidase, α-amylase, and tyrosinase. Docking studies were performed to tyrosinase, on the major metabolites, and samples were tested for antioxidant properties. Extracts were not toxic, were constituted mainly by flavonoids, and some compounds (roseoside and oleuropein) are here described for the first time in the species. The aerial organs’ ethanol extract had relevant activity towards 2,2-diphenyl-1-picrylhydrazyl [DPPH, half maximal inhibitory concentration (IC50) = 0.59 mg/mL], and ferric-reducing activity power (FRAP, IC50 = 0.99 mg/mL). All samples were more active towards AChE than on BuChE. The ethanol fruits’ extract inhibited α-glucosidase [2.19 mmol of equivalent of acarbose (ACAE)/g]. Samples were active against tyrosinase, especially the aerial organs’ ethanol extracts [25.9 mg of equivalent of kojic acid (KAE)/g]. Quercetin and kaempferol glycosides fit well into the enzymatic pocket of tyrosinase. Our results suggest sea rocket as a candidate to be further explored as a source of bioactive products.

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Section: Adme Estimationsupporting

confidence: 80%

Phenolic Profile, Toxicity, Enzyme Inhibition, In Silico Studies, and Antioxidant Properties of Cakile maritima Scop. (Brassicaceae) from Southern Portugal

Placines

Castañeda-Loaiza

Rodrigues

et al. 2020

Plants

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“…An interesting study addressed by Poli et al (2019), used virtual screening as a method to filter the compounds with the greatest potential to be tested experimentally. Considered one of the first examples of virtual screening studies focused on the identification of new peptide ligands as opioid modulators, the authors used parallel virtual screening from an internal library.…”

Section: Different Molecular Docking Approaches Applied To Antinocicementioning

confidence: 99%

Antinociceptive Activity of Chemical Components of Essential Oils That Involves Docking Studies: A Review

et al. 2020

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Introduction: Pain is considered an unpleasant sensory and emotional experience, being considered as one of the most important causes of human suffering. Computational chemistry associated with bioinformatics has stood out in the process of developing new drugs, through natural products, to manage this condition. Objective: To analyze, through literature data, recent molecular coupling studies on the antinociceptive activity of essential oils and monoterpenes. Data source: Systematic search of the literature considering the years of publications between 2005 and December 2019, in the electronic databases PubMed and Science Direct. Eligibility Criteria: Were considered as criteria of 1) Biological activity: non-clinical effects of an OE and/or monoterpenes on antinociceptive activity based on animal models and in silico analysis, 2) studies with plant material: chemically characterized essential oils and/or their constituents isolated, 3) clinical and non-clinical studies with in silico analysis to assess antinociceptive activity, 4) articles published in English. Exclusion criteria were literature review, report or case series, meta-analysis, theses, dissertations, and book chapter. Results: Of 16,006 articles, 16 articles fulfilled all the criteria. All selected studies were non-clinical. The most prominent plant families used were Asteraceae, Euphorbiaceae, Verbenaceae, Lamiaceae, and Lauraceae. Among the phytochemicals studied were a-Terpineol, 3-(5-substituted-1,3,4-oxadiazol-2-yl)-N′-[2-oxo-1,2-dihydro-3H-indol-3ylidene] propane hydrazide, b-cyclodextrin complexed with citronellal, (−)-a-bisabolol, b-cyclodextrin complexed with farnesol, and p-Cymene. The softwares used for docking studies were Molegro Virtual Docker, Sybyl ® X, Vlife MDS, AutoDock Vina, Hex Protein Docking, and AutoDock 4.2 in PyRx 0.9. The molecular targets/complexes used were Nitric Oxide Synthase, COX-2, GluR2-S1S2, TRPV1, b-CD complex, CaV 1 , CaV 2.1 , CaV 2.2 , and CaV 2.3 , 5-HT receptor, delta receptor, kappa receptor, and MU (m)

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“…Structure-based drug design employs methods of receptor-based virtual screening (VS) and molecular docking for binding pose prediction, hit identification, and lead optimization. As part of our ongoing effort to discover new κ modulators with novel structures [ 40 ], the study herein is focused on the crystal structure of the KOR active-state for the discovery of novel KOR ligands using VS ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands

et al. 2021

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The kappa opioid receptor (KOR) represents an attractive target for the development of drugs as potential antidepressants, anxiolytics and analgesics. A robust computational approach may guarantee a reduction in costs in the initial stages of drug discovery, novelty and accurate results. In this work, a virtual screening workflow of a library consisting of ~6 million molecules was set up, with the aim to find potential lead compounds that could manifest activity on the KOR. This in silico study provides a significant contribution in the identification of compounds capable of interacting with a specific molecular target. The main computational techniques adopted in this experimental work include: (i) virtual screening; (ii) drug design and leads optimization; (iii) molecular dynamics. The best hits are tripeptides prepared via solution phase peptide synthesis. These were tested in vivo, revealing a good antinociceptive effect after subcutaneous administration. However, further work is due to delineate their full pharmacological profile, in order to verify the features predicted by the in silico outcomes.

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Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Cited by 20 publications

References 40 publications

Phenolic Profile, Toxicity, Enzyme Inhibition, In Silico Studies, and Antioxidant Properties of Cakile maritima Scop. (Brassicaceae) from Southern Portugal

Phenolic Profile, Toxicity, Enzyme Inhibition, In Silico Studies, and Antioxidant Properties of Cakile maritima Scop. (Brassicaceae) from Southern Portugal

Antinociceptive Activity of Chemical Components of Essential Oils That Involves Docking Studies: A Review

In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands

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