Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors

Liu, Wen-Shan; Wang, Ruirui; Yan, Hai; Zheng, Zhaohui; Lu, Xinhua; Wang, Shuqing; Dong, Wen‐Kui; Wang, Run‐Ling

doi:10.1080/07391102.2019.1664333

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…The rest of ligand’s terminal aromatic scaffolds were in right orientations at the Tyr-P subsite replicating the reported hydrophobic interactions of the co-crystallized ligand, despite the little twisted orientation of the p -fluorophenyl group. Validation of the docking protocol was further confirmed through depicting residue-wise ligand–target binding interactions consistent with several reported studies introducing small compounds with potential or even actual PTP-1B inhibition activity [ 92 , 93 , 94 , 95 ]. The synthesized 4-thiazolinone derivatives introduced by Liu et al furnished significant PTP-1B inhibition activity with potencies down to one-digit micromolar concentrations (IC50 = 0.92–9.64 μM) with remarkable selectivity profiles over several PTPase targets [ 92 ].…”

Section: Resultssupporting

confidence: 75%

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach

et al. 2023

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Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL’s binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites’ extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound’s pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

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Section: Resultssupporting

confidence: 75%

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach

et al. 2023

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“…The P-loop is a rigid region of the PTP1B, and the binding of the flavonoid glycosides in this study appears to maintain that rigidity with negligible fluctuation which is an indication of good conformational behavior which in turn is indicative of enhanced stability of the complexes. Additionally, it was suggested by Liu et al [50] that lower fluctuations at this active region could potentiate a decrease in the catalytic activity of the enzyme which favors a PTP1B inhibitor as was the case in this study. In accordance with one of the prerequisites of PTP1B inhibitors, the WPD loop (an established flexible region of PTP1B) must adopt a stable conformation upon the binding of an inhibitor.…”

Section: Resultssupporting

confidence: 66%

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Rampadarath

Balogun

Pillay

et al. 2022

Journal of Diabetes Research

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Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signaling pathway, has gained attention as a validated druggable target in the management of type 2 diabetes mellitus (T2DM). The lack of clinically approved PTP1B inhibitors has continued to prompt research in plant-derived therapeutics possibly due to their relatively lesser toxicity profiles. Flavonoid C-glycosides are one of the plant-derived metabolites gaining increased relevance as antidiabetic agents, but their possible mechanism of action remains largely unknown. This study investigates the antidiabetic potential of flavonoid C-glycosides against PTP1B in silico and in vitro. Of the seven flavonoid C-glycosides docked against the enzyme, three compounds (apigenin, vitexin, and orientin) had the best affinity for the enzyme with a binding score of –7.3 kcal/mol each, relative to –7.4 kcal/mol for the reference standard, ursolic acid. A further probe (in terms of stability, flexibility, and compactness) of the complexes over a molecular dynamics time study of 100 ns for the three compounds suggested orientin as the most outstanding inhibitor of PTP1B owing to its overall -34.47 kcal/mol binding energy score compared to ursolic acid (-19.24 kcal/mol). This observation was in accordance with the in vitro evaluation result, where orientin had a half maximal inhibitory concentration (IC50) of 0.18 mg/ml relative to 0.13 mg/ml for the reference standard. The kinetics of inhibition of PTP1B by orientin was mixed-type with V max and K m values of 0.004 μM/s and 0.515 μM. Put together, the results suggest orientin as a potential PTP1B inhibitor and could therefore be further explored in the management T2DM as a promising therapeutic agent.

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“…(A) Three-dimensional (3D) docking pose of compound 108a bind to the catalytic site of PTP1B and simultaneously to the second aryl phosphorylate site. (B) Two-dimensional (2D) diagram of docking pose of compounds 108a.Liu et al[162] reported a series of 4-thiazolinone derivatives (109a-e, Figure45) with high PTP1B inhibitory activity (IC 50 values < 3 µM). Compound 109e was the most active PTP1B inhibitor with an IC 50 value of 0.92 µM.…”

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confidence: 99%

Thiazole Ring—A Biologically Active Scaffold

2021

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Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. Objective: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. Results: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.

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Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors

Cited by 8 publications

References 51 publications

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Thiazole Ring—A Biologically Active Scaffold

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