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15 pages, 3661 KiB

Open AccessArticle

Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L

by Ittipat Meewan, Jacob Kattoula, Julius Y. Kattoula, Danielle Skinner, Pavla Fajtová, Miriam A. Giardini, Brendon Woodworth, James H. McKerrow, Jair Lage de Siqueira-Neto, Anthony J. O’Donoghue and Ruben Abagyan

Pharmaceuticals 2022, 15(6), 744; https://doi.org/10.3390/ph15060744 - 13 Jun 2022

Cited by 7 | Viewed by 3455

Abstract

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 [...] Read more.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC₅₀s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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31 pages, 10654 KiB

Open AccessArticle

Design, Synthesis, and In Vitro, In Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors

by Martina Bortolami, Fabiana Pandolfi, Valeria Tudino, Antonella Messore, Valentina Noemi Madia, Daniela De Vita, Roberto Di Santo, Roberta Costi, Isabella Romeo, Stefano Alcaro, Marisa Colone, Annarita Stringaro, Alba Espargaró, Raimon Sabatè and Luigi Scipione

Pharmaceuticals 2022, 15(6), 673; https://doi.org/10.3390/ph15060673 - 27 May 2022

Cited by 3 | Viewed by 3023

Abstract

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase [...] Read more.

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ₄₂ and tau and to be able to chelate Cu²⁺ and Fe³⁺ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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18 pages, 6913 KiB

Open AccessArticle

Network Pharmacology and Bioinformatics Approach Reveals the Multi-Target Pharmacological Mechanism of Fumaria indica in the Treatment of Liver Cancer

by Sara Batool, Muhammad Rizwan Javed, Sidra Aslam, Fatima Noor, Hafiz Muhammad Faizan Javed, Riffat Seemab, Abdur Rehman, Muhammad Farhan Aslam, Bilal Ahamad Paray and Aneela Gulnaz

Pharmaceuticals 2022, 15(6), 654; https://doi.org/10.3390/ph15060654 - 25 May 2022

Cited by 24 | Viewed by 9005

Abstract

Liver cancer (LC), a frequently occurring cancer, has become the fourth leading cause of cancer mortality. The small number of reported data and diverse spectra of pathophysiological mechanisms of liver cancer make it a challenging task and a serious economic burden in health [...] Read more.

Liver cancer (LC), a frequently occurring cancer, has become the fourth leading cause of cancer mortality. The small number of reported data and diverse spectra of pathophysiological mechanisms of liver cancer make it a challenging task and a serious economic burden in health care management. Fumaria indica is a herbaceous annual plant used in various regions of Asia to treat a variety of ailments, including liver cancer. Several in vitro investigations have revealed the effectiveness of F. indica in the treatment of liver cancer; however, the exact molecular mechanism is still unrevealed. In this study, the network pharmacology technique was utilized to characterize the mechanism of F. indica on liver cancer. Furthermore, we analyzed the active ingredient-target-pathway network and uncovered that Fumaridine, Lastourvilline, N-feruloyl tyramine, and Cryptopine conclusively contributed to the development of liver cancer by affecting the MTOR, MAPK3, PIK3R1, and EGFR gene. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. The results of molecular docking predicted that several key targets of liver cancer (along with MTOR, EGFR, MAPK3, and PIK3R1) bind stably with the corresponding active ingredient of F. indica. We concluded through network pharmacology methods that multiple biological processes and signaling pathways involved in F. indica exerted a preventing effect in the treatment of liver cancer. The molecular docking results also provide us with sound direction for further experiments. In the framework of this study, network pharmacology integrated with docking analysis revealed that F. indica exerted a promising preventive effect on liver cancer by acting on liver cancer-associated signaling pathways. This enables us to understand the biological mechanism of the anti liver cancer activity of F. indica. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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23 pages, 3889 KiB

Open AccessArticle

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

by Anna Sampietro, F. Javier Pérez-Areales, Paula Martínez, Elsa M. Arce, Carles Galdeano and Diego Muñoz-Torrero

Pharmaceuticals 2022, 15(5), 545; https://doi.org/10.3390/ph15050545 - 28 Apr 2022

Cited by 25 | Viewed by 5223

Abstract

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990–2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed [...] Read more.

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990–2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3β, NMDA receptors, and more than 70 other targets have been only marginally considered. These results might allow us to spot new design opportunities based on innovative target combinations to expand and diversify the repertoire of multitarget drug candidates and increase the likelihood of finding effective therapies for this devastating disease. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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17 pages, 5897 KiB

Open AccessArticle

Integrating Network Pharmacology and Molecular Docking Approaches to Decipher the Multi-Target Pharmacological Mechanism of Abrus precatorius L. Acting on Diabetes

by Fatima Noor, Abdur Rehman, Usman Ali Ashfaq, Muhammad Hamzah Saleem, Mohammad K. Okla, Abdulrahman Al-Hashimi, Hamada AbdElgawad and Sidra Aslam

Pharmaceuticals 2022, 15(4), 414; https://doi.org/10.3390/ph15040414 - 29 Mar 2022

Cited by 44 | Viewed by 7392

Abstract

Type 2 diabetes mellitus (T2DM) is a notable health care load that imposes a serious impact on the quality of life of patients. The small amount of reported data and multiple spectra of pathophysiological mechanisms of T2DM make it a challenging task and [...] Read more.

Type 2 diabetes mellitus (T2DM) is a notable health care load that imposes a serious impact on the quality of life of patients. The small amount of reported data and multiple spectra of pathophysiological mechanisms of T2DM make it a challenging task and serious economic burden in health care management. Abrus precatorius L. is a slender, perennial, deciduous, and woody twining plant used in various regions of Asia to treat a variety of ailments, including diabetes mellitus. Various in vitro studies revealed the therapeutic significance of A. precatorius against diabetes. However, the exact molecular mechanism remains unclarified. In the present study, a network pharmacology technique was employed to uncover the active ingredients, their potential targets, and signaling pathways in A. precatorius for the treatment of T2DM. In the framework of this study, we explored the active ingredient–target–pathway network and figured out that abrectorin, abrusin, abrisapogenol J, sophoradiol, cholanoic acid, precatorine, and cycloartenol decisively contributed to the development of T2DM by affecting AKT1, MAPK3, TNFalpha, and MAPK1 genes. Later, molecular docking was employed to validate the successful activity of the active compounds against potential targets. Lastly, we conclude that four highly active constituents, namely, abrusin, abrisapogenol J, precatorine, and cycloartenol, help in improving the body’s sensitivity to insulin and regulate the expression of AKT1, MAPK3, TNFalpha, and MAPK1, which may act as potential therapeutic targets of T2DM. Integrated network pharmacology and docking analysis revealed that A. precatorius exerted a promising preventive effect on T2DM by acting on diabetes-associated signaling pathways. This provides a basis to understand the mechanism of the anti-diabetes activity of A. precatorius. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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20 pages, 2444 KiB

Open AccessArticle

Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain

by Young-Hwan Jung, Yeo Ok Kim, Koon Mook Kang, Hyung Gon Lee, Borum Son, Xuehao Han, Eunseok Oh, Siwon Kim, Seon Hee Seo, Jong-Hyun Park, Ki Duk Park, Woong Mo Kim, Myung Ha Yoon and Yong-Chul Kim

Pharmaceuticals 2022, 15(4), 407; https://doi.org/10.3390/ph15040407 - 27 Mar 2022

Viewed by 2898

Abstract

Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an [...] Read more.

Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (μ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, 17, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC₅₀ values of 70 nM, 154 nM and 2.01 μM at hSERT, hNET and hDAT, respectively. Additionally, compound 17 showed partial agonism (EC₅₀ = 384 nM) at the μ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound 17 showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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20 pages, 2711 KiB

Open AccessArticle

Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1–7 via PI3K/AKT/mTOR Signaling Pathway

by Yasmin M. Ahmed, Mohamed A. Abdelgawad, Khaled Shalaby, Mohammed M. Ghoneim, Asmaa M. AboulMagd, Nada S. Abdelwahab, Hossam M. Hassan and Asmaa M. Othman

Pharmaceuticals 2022, 15(3), 341; https://doi.org/10.3390/ph15030341 - 10 Mar 2022

Cited by 5 | Viewed by 3012

Abstract

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study [...] Read more.

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1–7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1–7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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15 pages, 8827 KiB

Open AccessArticle

STW 5 Herbal Preparation Modulates Wnt3a and Claudin 1 Gene Expression in Zebrafish IBS-like Model

by Monica Piccione, Nicola Facchinello, Sandra Schrenk, Marco Gasparella, Surajit Pathak, Ramy M. Ammar, Sabine Rabini, Luisa Dalla Valle and Rosa Di Liddo

Pharmaceuticals 2021, 14(12), 1234; https://doi.org/10.3390/ph14121234 - 28 Nov 2021

Viewed by 3067

Abstract

Aim: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal pain and stool irregularities. STW 5 has proven clinical efficacy in functional gastrointestinal disorders, including IBS, targeting pathways that suppress inflammation and protect the mucosa. Wnt signaling is known [...] Read more.

Aim: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal pain and stool irregularities. STW 5 has proven clinical efficacy in functional gastrointestinal disorders, including IBS, targeting pathways that suppress inflammation and protect the mucosa. Wnt signaling is known to modulate NF-kβ-dependent inflammatory cytokine production. This sparked the idea of evaluating the impact of STW 5 on the expression of inflammatory-response and Wnt/β catenin-target genes in an IBS-like model. Main methods: We used zebrafish and dextran sodium sulfate (DSS) treatment to model IBS-like conditions in vivo and in vitro and examined the effects of subsequent STW 5 treatment on the intestines of DSS-treated fish and primary cultured intestinal and neuronal cells. Gross gut anatomy, histology, and the expression of Wnt-signaling and cytokine genes were analyzed in treated animals and/or cells, and in controls. Key findings: DSS treatment up-regulated the expression of interleukin-8, tumor necrosis factor-α, wnt3a, and claudin-1 in explanted zebrafish gut. Subsequent STW 5 treatment abolished both the macroscopic signs of gut inflammation, DSS-induced mucosecretory phenotype, and normalized the DSS-induced upregulated expression of il10 and Wnt signaling genes, such as wnt3a and cldn1 in explanted zebrafish gut. Under inflammatory conditions, STW 5 downregulated the expression of the pro-inflammatory cytokine genes il1β, il6, il8, and tnfα while it upregulated the expression of the anti-inflammatory genes il10 and wnt3a in enteric neuronal cells in vitro. Significance: Wnt signaling could be a novel target for the anti-inflammatory and intestinal permeability-restoring effects of STW 5, possibly explaining its clinical efficacy in IBS. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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28 pages, 4545 KiB

Open AccessArticle

The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

by Egils Bisenieks, Brigita Vigante, Ramona Petrovska, Baiba Turovska, Ruslan Muhamadejev, Vitalijs Soloduns, Astrida Velena, Karlis Pajuste, Luciano Saso, Janis Klovins, Gunars Duburs and Ilona Mandrika

Pharmaceuticals 2021, 14(10), 987; https://doi.org/10.3390/ph14100987 - 28 Sep 2021

Cited by 5 | Viewed by 2978

Abstract

The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have been synthesized in order to characterise their pleiotropic, multitarget [...] Read more.

The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have been synthesized in order to characterise their pleiotropic, multitarget activity on the FFA3/GPR41, FFA2/GPR43, and HCA2/GPR109A receptors. Hexahydroquinoline derivatives have been known to exhibit characteristic activity as FFA3/GPR41 ligands, but during this study we observed their impact on FFA2/GPR43 and HCA2/GPR109A receptors as well as their electron-donating activity. Oxopyranopyrimidine and thioxopyranopyrimidine type compounds have been studied as ligands of the HCA2/GPR109A receptor; nevertheless, they exhibited equal or higher activity towards FFA3/GPR41 and FFA2/GPR43 receptors. S-Alkyl derivatives of pyranopyrimidines that have not yet been studied as ligands of GPCRs were more active towards HCA2/GPR109A and FFA3/GPR41 receptors than towards FFA2/GPR43. Representative compounds from each synthesized series were able to decrease the lipopolysaccharide-induced gene expression and secretion of proinflammatory cytokines (IL-6, TNF-α) and of a chemokine (MCP-1) in THP-1 macrophages, resembling the effect of HCA2/GPR109A ligand niacin and the endogenous ligand propionate. This study revealed groups of compounds possessing multitarget activity towards several receptors. The obtained data could be useful for further development of multitarget ligands. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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18 pages, 4356 KiB

Open AccessArticle

In Silico-Based Design and In Vivo Evaluation of an Anthranilic Acid Derivative as a Multitarget Drug in a Diet-Induced Metabolic Syndrome Model

by Héctor González-Álvarez, Astrid Bravo-Jiménez, Matilda Martínez-Arellanes, Gabriela Odette Gamboa-Osorio, Edwin Chávez-Gutiérrez, Lino A. González-Hernández, Karina Gallardo-Ignacio, Osvaldo J. Quintana-Romero, Armando Ariza-Castolo, Christian Guerra-Araiza, Laura Martino-Roaro, Dulce María Meneses-Ruiz, Rodolfo Pinto-Almazán and Marco A. Loza-Mejía

Pharmaceuticals 2021, 14(9), 914; https://doi.org/10.3390/ph14090914 - 10 Sep 2021

Cited by 7 | Viewed by 4927

Abstract

Metabolic syndrome (MetS) is a complex disease that affects almost a quarter of the world’s adult population. In MetS, diabetes, obesity, hyperglycemia, high cholesterol, and high blood pressure are the most common disorders. Polypharmacy is the most used strategy for managing conditions related [...] Read more.

Metabolic syndrome (MetS) is a complex disease that affects almost a quarter of the world’s adult population. In MetS, diabetes, obesity, hyperglycemia, high cholesterol, and high blood pressure are the most common disorders. Polypharmacy is the most used strategy for managing conditions related to MetS, but it has drawbacks such as low medication adherence. Multitarget ligands have been proposed as an interesting approach to developing drugs to treat complex diseases. However, suitable preclinical models that allow their evaluation in a context closer to a clinical situation of a complex disease are needed. From molecular docking studies, compound 1b, a 5-aminoanthranilic acid derivative substituted with 4′-trifluoromethylbenzylamino and 3′,4′-dimethoxybenzamide moieties, was identified as a potential multitarget drug, as it showed high in silico affinity against targets related to MetS, including PPAR-α, PPAR-γ, and HMG-CoA reductase. It was evaluated in a diet-induced MetS rat model and simultaneously lowered blood pressure, glucose, total cholesterol, and triglyceride levels after a 14-day treatment. No toxicity events were observed during an acute lethal dose evaluation test at 1500 mg/kg. Hence, the diet-induced MetS model is suitable for evaluating treatments for MetS, and compound 1b is an attractive starting point for developing multitarget drugs. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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25 pages, 7124 KiB

Open AccessArticle

Selective DNA Gyrase Inhibitors: Multi-Target in Silico Profiling with 3D-Pharmacophores

by Tihomir Tomašič, Asta Zubrienė, Žiga Skok, Riccardo Martini, Stane Pajk, Izidor Sosič, Janez Ilaš, Daumantas Matulis and Sharon D. Bryant

Pharmaceuticals 2021, 14(8), 789; https://doi.org/10.3390/ph14080789 - 10 Aug 2021

Cited by 6 | Viewed by 4353

Abstract

DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors [...] Read more.

DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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11 pages, 3765 KiB

Open AccessArticle

Aryl Urea Based Scaffolds for Multitarget Drug Discovery in Anticancer Immunotherapies

by Celia Martín-Beltrán, Raquel Gil-Edo, Germán Hernández-Ribelles, Raül Agut, Pilar Marí-Mezquita, Miguel Carda and Eva Falomir

Pharmaceuticals 2021, 14(4), 337; https://doi.org/10.3390/ph14040337 - 6 Apr 2021

Cited by 10 | Viewed by 2500

Abstract

Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as multitarget inhibitors of Vascular endothelial growth factor receptor-2 VEGFR-2 and programmed death-ligand-1 (PD-L1) proteins in order to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on [...] Read more.

Twenty-one styryl and phenethyl aryl ureas have been synthetized and biologically evaluated as multitarget inhibitors of Vascular endothelial growth factor receptor-2 VEGFR-2 and programmed death-ligand-1 (PD-L1) proteins in order to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, MCF-7, HeLa and A549), on the endothelial cell line human microvascular endothelial cells (HMEC)-1 and on the non-tumor cell line human embryonic kidney cells (HEK)-293 has been determined. Some derivatives were evaluated for their antiangiogenic properties such as their ability to inhibit microvessel formation using HMEC-1 or their effect on VEGFR-2 in both cancer and endothelial cell lines. In addition, the immunomodulator action of a number of selected compounds was also studied on PD-L1 and c-Myc proteins. Compounds 16 and 23 (Z) and (E)-styryl p-bromophenyl urea, respectively, showed better results than sorafenib in down-regulation of VEGFR-2 and also improved the effect of the anti-PD-L1 compound BMS-8 on both targets, PD-L1 and c-Myc proteins. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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22 pages, 2094 KiB

Open AccessArticle

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

by Paloma Begines, Lucía Sevilla-Horrillo, Adrián Puerta, Rebecca Puckett, Samuel Bayort, Irene Lagunes, Inés Maya, José M. Padrón, Óscar López and José G. Fernández-Bolaños

Pharmaceuticals 2020, 13(11), 358; https://doi.org/10.3390/ph13110358 - 31 Oct 2020

Cited by 12 | Viewed by 2995

Abstract

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial [...] Read more.

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI₅₀ = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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28 pages, 4508 KiB

Open AccessArticle

Novel Sulfonamide-Based Analogs of Metformin Exert Promising Anti-Coagulant Effects without Compromising Glucose-Lowering Activity

by Magdalena Markowicz-Piasecka, Adrianna Sadkowska, Joanna Sikora, Marlena Broncel and Kristiina M. Huttunen

Pharmaceuticals 2020, 13(10), 323; https://doi.org/10.3390/ph13100323 - 21 Oct 2020

Cited by 10 | Viewed by 3537

Abstract

Metformin, one of the most frequently prescribed oral anti-diabetic drugs, is characterized by multidirectional activity, including lipid lowering, cardio-protective and anti-inflammatory properties. This study presents synthesis and stability studies of 10 novel sulfonamide-based derivatives of metformin with alkyl substituents in the aromatic ring. [...] Read more.

Metformin, one of the most frequently prescribed oral anti-diabetic drugs, is characterized by multidirectional activity, including lipid lowering, cardio-protective and anti-inflammatory properties. This study presents synthesis and stability studies of 10 novel sulfonamide-based derivatives of metformin with alkyl substituents in the aromatic ring. The potential of the synthesized compounds as glucose-lowering agents and their effects on selected parameters of plasma and vascular hemostasis were examined. Compounds with two or three methyl groups in the aromatic ring (6, 7, 9, 10) significantly increased glucose uptake in human umbilical vein endothelial cells (HUVECs), e.g., 15.8 µmol/L for comp. 6 at 0.3 µmol/mL versus 11.4 ± 0.7 µmol/L for control. Basic coagulation studies showed that all examined compounds inhibit intrinsic coagulation pathway and the process of fibrin polymerization stronger than the parent drug, metformin, which give evidence of their greater anti-coagulant properties. Importantly, synthesized compounds decrease the activity of factor X, a first member of common coagulation pathway, while metformin does not affect coagulation factor X (FX) activity. A multiparametric clot formation and lysis test (CL-test) revealed that the examined compounds significantly prolong the onset of clot formation; however, they do not affect the overall potential of clot formation and fibrinolysis. Erythrotoxicity studies confirmed that none of the synthesized compounds exert an adverse effect on erythrocyte integrity, do not contribute to the massive hemolysis and do not interact strongly with the erythrocyte membrane. In summary, chemical modification of metformin scaffold into benzenesulfonamides containing alkyl substituents leads to the formation of potential dual-action agents with comparable glucose-lowering properties and stronger anti-coagulant activity than the parent drug, metformin. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus

by Jana Blahova, Monika Martiniakova, Martina Babikova, Veronika Kovacova, Vladimira Mondockova and Radoslav Omelka

Pharmaceuticals 2021, 14(8), 806; https://doi.org/10.3390/ph14080806 - 17 Aug 2021

Cited by 141 | Viewed by 19221

Abstract

Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin [...] Read more.

Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium–glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes

by Anand-Krishna Singh, Dhananjay Yadav, Neha Sharma and Jun-O Jin

Pharmaceuticals 2021, 14(6), 586; https://doi.org/10.3390/ph14060586 - 18 Jun 2021

Cited by 49 | Viewed by 8597

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia that is predominantly caused by insulin resistance or impaired insulin secretion, along with disturbances in carbohydrate, fat and protein metabolism. Various therapeutic approaches have been used to treat diabetes, including improvement of insulin sensitivity, [...] Read more.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia that is predominantly caused by insulin resistance or impaired insulin secretion, along with disturbances in carbohydrate, fat and protein metabolism. Various therapeutic approaches have been used to treat diabetes, including improvement of insulin sensitivity, inhibition of gluconeogenesis, and decreasing glucose absorption from the intestines. Recently, a novel approach has emerged using dipeptidyl peptidase-IV (DPP-IV) inhibitors as a possible agent for the treatment of T2DM without producing any side effects, such as hypoglycemia and exhaustion of pancreatic β-cells. DPP-IV inhibitors improve hyperglycemic conditions by stabilizing the postprandial level of gut hormones such as glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptides, which function as incretins to help upregulate insulin secretion and β-cell mass. In this review, we summarized DPP-IV inhibitors and their mechanism of inhibition, activities of those isolated from various natural sources, and their capacity to overcome oxidative stress in disease conditions. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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