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Molecular Targets and Drug Discovery for Metabolic Disorders: Challenges, Recent Developments, and Prospects

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 5439

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Special Issue Editors

Dr. Rosanna Maccari

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (ChiBioFarAm), University of Messina, Messina, Italy
Interests: medicinal chemistry; drug design and discovery; structure-activity relationships; enzyme inhibitors; antidiabetic agents; anti-inflammatory agents; anticancer agents; multitarget agents
Special Issues, Collections and Topics in MDPI journals

Dr. Rosaria Ottana

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (ChiBioFarAm), University of Messina, Messina, Italy
Interests: medicinal chemistry; drug design and discovery; structure-activity relationships; enzyme inhibitors; antidiabetic agents; anti-inflammatory agents; multitarget agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolic disorders include a wide variety of diseases, such as diabetes mellitus, obesity, and dyslipidemia, which are often associated with metabolic syndrome. These conditions are a leading cause of severe cardiovascular complications, neurodegeneration, and cancer. Currently, they affect several million people worldwide and the incidence of some of them, particularly type 2 diabetes and obesity, has increased dramatically in recent decades. Overall, metabolic disorders and the associated complications constitute a serious global health threat; therefore, continuous research efforts are required to develop novel therapeutic strategies. The current therapy for some of these disorders, such as diabetes, can only slow the disease progression; moreover, the clinical use of certain available drugs can be accompanied by the occurrence of undesired side effects or limited efficacy in controlling metabolic dysfunctions in some patients. The identification of new molecular targets implicated in the complex pathogenetic pathways underlying these diseases can critically contribute to the development of novel drugs in this field. This Special Issue aims to focus on recent advancements and prospects in the design and development of agents for treating metabolic disorders, as well as providing insight into new molecular targets and drug discovery approaches. Original research papers, short communications, and review articles are welcome.

Dr. Rosanna Maccari
Dr. Rosaria Ottana
Guest Editors

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Keywords

metabolic disorders
drug design
drug discovery
drug synthesis
lead generation
lead optimization
molecular targets
structure–activity relationships

Published Papers (3 papers)

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Research

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12 pages, 2565 KiB

Open AccessArticle

Identification of GM1-Ganglioside Secondary Accumulation in Fibroblasts from Neuropathic Gaucher Patients and Effect of a Trivalent Trihydroxypiperidine Iminosugar Compound on Its Storage Reduction

by Costanza Ceni, Francesca Clemente, Francesca Mangiavacchi, Camilla Matassini, Rodolfo Tonin, Anna Caciotti, Federica Feo, Domenico Coviello, Amelia Morrone, Francesca Cardona and Martino Calamai

Molecules 2024, 29(2), 453; https://doi.org/10.3390/molecules29020453 - 17 Jan 2024

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Abstract

Gaucher disease (GD) is a rare genetic metabolic disorder characterized by a dysfunction of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) due to mutations in the gene GBA1, leading to the cellular accumulation of glucosylceramide (GlcCer). While most of the current research focuses on the primary accumulated material, lesser attention has been paid to secondary storage materials and their reciprocal intertwining. By using a novel approach based on flow cytometry and fluorescent labelling, we monitored changes in storage materials directly in fibroblasts derived from GD patients carrying N370S/RecNcil and homozygous L444P or R131C mutations with respect to wild type. In L444P and R131C fibroblasts, we detected not only the primary accumulation of GlcCer accumulation but also a considerable secondary increase in GM1 storage, comparable with the one observed in infantile patients affected by GM1 gangliosidosis. In addition, the ability of a trivalent trihydroxypiperidine iminosugar compound (CV82), which previously showed good pharmacological chaperone activity on GCase enzyme, to reduce the levels of storage materials in L444P and R131C fibroblasts was tested. Interestingly, treatment with different concentrations of CV82 led to a significant reduction in GM1 accumulation only in L444P fibroblasts, without significantly affecting GlcCer levels. The compound CV82 was selective against the GCase enzyme with respect to the β-Galactosidase enzyme, which was responsible for the catabolism of GM1 ganglioside. The reduction in GM1-ganglioside level cannot be therefore ascribed to a direct action of CV82 on β-Galactosidase enzyme, suggesting that GM1 decrease is rather related to other unknown mechanisms that follow the direct action of CV82 on GCase. In conclusion, this work indicates that the tracking of secondary storages can represent a key step for a better understanding of the pathways involved in the severity of GD, also underlying the importance of developing drugs able to reduce both primary and secondary storage-material accumulations in GD. Full article

(This article belongs to the Special Issue Molecular Targets and Drug Discovery for Metabolic Disorders: Challenges, Recent Developments, and Prospects)

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16 pages, 3119 KiB

Open AccessArticle

Design, Synthesis, Computational and Biological Evaluation of Novel Structure Fragments Based on Lithocholic Acid (LCA)

by Jiangling Peng, Mingjie Fan, Kelly X. Huang, Lina A. Huang, Yangmeng Wang, Runkai Yin, Hanyi Zhao, Senlin Xu, Hongzhi Li, Alon Agua, Jun Xie, David A. Horne, Fouad Kandeel, Wendong Huang and Junfeng Li

Molecules 2023, 28(14), 5332; https://doi.org/10.3390/molecules28145332 - 11 Jul 2023

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Abstract

The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar “oxygen atom” into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a–1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a–1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing. Full article

(This article belongs to the Special Issue Molecular Targets and Drug Discovery for Metabolic Disorders: Challenges, Recent Developments, and Prospects)

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Review

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43 pages, 20592 KiB

Open AccessReview

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents

by Vishal Mathur, Ozair Alam, Nadeem Siddiqui, Mukund Jha, Ajay Manaithiya, Sandhya Bawa, Naveen Sharma, Sultan Alshehri, Prawez Alam and Faiyaz Shakeel

Molecules 2023, 28(15), 5860; https://doi.org/10.3390/molecules28155860 - 03 Aug 2023

Cited by 4 | Viewed by 2766

Abstract

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC₅₀) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future. Full article

(This article belongs to the Special Issue Molecular Targets and Drug Discovery for Metabolic Disorders: Challenges, Recent Developments, and Prospects)

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