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Metalloenzyme Inhibitors and Activators II

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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: closed (31 December 2021) | Viewed by 52841

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Prof. Dr. Elisa Nuti

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Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: medicinal chemistry; metallo-enzyme inhibitors; drug discovery; synthesis of biologically active compounds; fluorescent probes
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Special Issue Information

Dear Colleagues,

Metalloenzymes represent a target of medicinal chemistry that have been extensively investigated in the last several decades. Since they are responsible for the regulation of a wide range of physiological processes, they are also involved in the development of many pathological conditions, including cancer, inflammation, microbial infections, and HIV/AIDS. Metalloenzymes are metalloproteins characterized by a functional metal ion that serves to promote catalysis. Achieving selectivity for a particular isoenzyme over other members of the same family is an issue that has hampered the clinical development of metalloenzyme inhibitors. Recent studies involving the resolution of enzyme crystal structures, site-directed mutagenesis of catalytic residues, and molecular modeling of catalytic domains have opened the way to the synthesis of more selective agents.

This Special Issue aims to collect the recent advances in the inhibition of metalloenzymes such as carbonic anhydrases, matrix metalloproteinases (MMPs), ADAMs (A Disintegrin-like And Metalloproteinases), ADAMTSs (ADAM with Thrombospondin-like motifs), histone deacetylases (HDACs), angiotensin-converting enzyme (ACE), and HIV-1 integrase, among others. Particularly welcome are studies involving the development of small molecules but also exosite inhibitors, glycoconjugates, as well as protein–protein interaction (PPI) inhibitors.

Prof. Dr. Elisa Nuti
Guest Editor

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Keywords

drug discovery
synthesis
structure–activity relationships
metalloenzyme inhibitors
carbonic anhydrase
MMP, ADAM
ADAMTS
HDAC
activators

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Published Papers (11 papers)

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16 pages, 1564 KiB

Open AccessArticle

Screening of Carbonic Anhydrase, Acetylcholinesterase, Butyrylcholinesterase, and α-Glycosidase Enzyme Inhibition Effects and Antioxidant Activity of Coumestrol

by Lokman Durmaz, Adem Erturk, Mehmet Akyüz, Leyla Polat Kose, Eda Mehtap Uc, Zeynebe Bingol, Ruya Saglamtas, Saleh Alwasel and İlhami Gulcin

Molecules 2022, 27(10), 3091; https://doi.org/10.3390/molecules27103091 - 11 May 2022

Cited by 53 | Viewed by 3549

Abstract

Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in plants. In this study, antiglaucoma, antidiabetic, anticholinergic, and antioxidant effects of Coumestrol were evaluated and compared with standards. To determine the antioxidant activity of coumestrol, several methods—namely N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD^•+)-scavenging activity, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS^•+)-scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH^•)-scavenging activity, potassium ferric cyanide reduction ability, and cupric ion (Cu²⁺)-reducing activity—were performed. Butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were used as the reference antioxidants for comparison. Coumestrol scavenged the DPPH radical with an IC₅₀ value of 25.95 μg/mL (r²: 0.9005) while BHA, BHT, Trolox, and α-Tocopherol demonstrated IC₅₀ values of 10.10, 25.95, 7.059, and 11.31 μg/mL, respectively. When these results evaluated, Coumestrol had similar DPPH^•-scavenging effect to BHT and lower better than Trolox, BHA and α-tocopherol. In addition, the inhibition effects of Coumestrol were tested against the metabolic enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which are associated with some global diseases such as Alzheimer’s disease (AD), glaucoma, and diabetes. Coumestrol exhibited K_i values of 10.25 ± 1.94, 5.99 ± 1.79, 25.41 ± 1.10, and 30.56 ± 3.36 nM towards these enzymes, respectively. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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18 pages, 5206 KiB

Open AccessArticle

Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

by Fatema Rahman, Imin Wushur, Nabin Malla, Ove Alexander Høgmoen Åstrand, Pål Rongved, Jan-Olof Winberg and Ingebrigt Sylte

Molecules 2022, 27(1), 56; https://doi.org/10.3390/molecules27010056 - 22 Dec 2021

Cited by 2 | Viewed by 3122

Abstract

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with K_i values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a K_i value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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17 pages, 1383 KiB

Open AccessFeature PaperArticle

Identification of Broad-Spectrum MMP Inhibitors by Virtual Screening

by Aleix Gimeno, Doretta Cuffaro, Elisa Nuti, María José Ojeda-Montes, Raúl Beltrán-Debón, Miquel Mulero, Armando Rossello, Gerard Pujadas and Santiago Garcia-Vallvé

Molecules 2021, 26(15), 4553; https://doi.org/10.3390/molecules26154553 - 28 Jul 2021

Cited by 7 | Viewed by 3047

Abstract

Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading extracellular matrix (ECM) components. In the skin, the overexpression of MMPs as a result of ultraviolet radiation triggers an imbalance in the ECM turnover in a process called photoaging, which ultimately results in skin wrinkling and premature skin ageing. Therefore, the inhibition of different enzymes of the MMP family at a topical level could have positive implications for photoaging. Considering that the MMP catalytic region is mostly conserved across different enzymes of the MMP family, in this study we aimed to design a virtual screening (VS) workflow to identify broad-spectrum MMP inhibitors that can be used to delay the development of photoaging. Our in silico approach was validated in vitro with 20 VS hits from the Specs library that were not only structurally different from one another but also from known MMP inhibitors. In this bioactivity assay, 18 of the 20 compounds inhibit at least one of the assayed MMPs at 100 μM (with 5 of them showing around 50% inhibition in all the tested MMPs at this concentration). Finally, this VS was used to identify natural products that have the potential to act as broad-spectrum MMP inhibitors and be used as a treatment for photoaging. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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13 pages, 2128 KiB

Open AccessArticle

The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening

by Sarah L. Mueller, Panagiotis K. Chrysanthopoulos, Maria A. Halili, Caryn Hepburn, Tom Nebl, Claudiu T. Supuran, Alessio Nocentini, Thomas S. Peat and Sally-Ann Poulsen

Molecules 2021, 26(10), 3010; https://doi.org/10.3390/molecules26103010 - 18 May 2021

Cited by 10 | Viewed by 3734

Abstract

The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SO₂NH₂) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen–deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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16 pages, 4068 KiB

Open AccessArticle

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study (Part II)

by Maywan Hariono, Rollando Rollando, I Yoga, Abraham Harjono, Alfonsus Suryodanindro, Michael Yanuar, Thomas Gonzaga, Zet Parabang, Pandu Hariyono, Rifki Febriansah, Adi Hermawansyah, Wahyuning Setyani and Habibah Wahab

Molecules 2021, 26(5), 1464; https://doi.org/10.3390/molecules26051464 - 8 Mar 2021

Cited by 14 | Viewed by 3001

Abstract

In our previous work, the partitions (1 mg/mL) of Ageratum conyzoides (AC) aerial parts and Ixora coccinea (IC) leaves showed inhibitions of 94% and 96%, respectively, whereas their fractions showed IC₅₀ 43 and 116 µg/mL, respectively, toward Matrix Metalloproteinase9 (MMP9), an enzyme that catalyzes a proteolysis of extracellular matrix. In this present study, we performed IC₅₀ determinations for AC n-hexane, IC n-hexane, and IC ethylacetate partitions, followed by the cytotoxicity study of individual partitions against MDA-MB-231, 4T1, T47D, MCF7, and Vero cell lines. Successive fractionations from AC n-hexane and IC ethylacetate partitions led to the isolation of two compounds, oxytetracycline (OTC) and dioctyl phthalate (DOP). The result showed that AC n-hexane, IC n-hexane, and IC ethylacetate partitions inhibit MMP9 with their respective IC₅₀ as follows: 246.1 µg/mL, 5.66 µg/mL, and 2.75 × 10⁻² µg/mL. Toward MDA-MB-231, 4T1, T47D, and MCF7, AC n-hexane demonstrated IC₅₀ 2.05, 265, 109.70, and 2.11 µg/mL, respectively, whereas IC ethylacetate showed IC₅₀ 1.92, 57.5, 371.5, and 2.01 µg/mL, respectively. The inhibitions toward MMP9 by OTC were indicated by its IC₅₀ 18.69 µM, whereas DOP was inactive. A molecular docking study suggested that OTC prefers to bind to PEX9 rather than its catalytic domain. Against 4T1, OTC showed inhibition with IC₅₀ 414.20 µM. In conclusion, this study furtherly supports the previous finding that AC and IC are two herbals with potential to be developed as triple-negative anti-breast cancer agents. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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18 pages, 2819 KiB

Open AccessArticle

Biochemical Properties of Tyrosinase from Aspergillus terreus and Penicillium copticola; Undecanoic Acid from Aspergillus flavus, an Endophyte of Moringa oleifera, Is a Novel Potent Tyrosinase Inhibitor

by Hanaa Salah Maamoun, Gamal H. Rabie, Ibrahim Shaker, Bothaina A. Alaidaroos and Ashraf S. A. El-Sayed

Molecules 2021, 26(5), 1309; https://doi.org/10.3390/molecules26051309 - 1 Mar 2021

Cited by 18 | Viewed by 2969

Abstract

Tyrosinase is a copper-containing monooxygenase catalyzing the O-hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine then to dopaquinone that is profoundly involved in melanin synthesis in eukaryotes. Overactivation of tyrosinase is correlated with hyperpigmentation that is metabolically correlated with severe pathological disorders, so, inhibition of this enzyme is the most effective approach in controlling the overproduction of melanin and its hazardous effects. Thus, searching for a powerful, selective inhibitor of human tyrosinase to limit the hyper-synthesis of melanin is a challenge. Unlike the difficulty of overexpression of human tyrosinase, using fungal tyrosinase as a model enzyme to the human one to evaluate the mechanistics of enzyme inhibition in response to various compounds is the most feasible strategy. Thus, the purification of highly catalytic-efficient fungal tyrosinase, exploring a novel inhibitor, and evaluating the mechanistics of enzyme inhibition are the main objectives of this work. Aspergillus terreus and Penicillium copticola were reported as the most potential tyrosinase producers. The biochemical properties suggest that this enzyme displays a higher structural and catalytic proximity to human tyrosinase. Upon nutritional bioprocessing by Plackett–Burman design, the yield of tyrosinase was increased by about 7.5-folds, compared to the control. The purified tyrosinase was strongly inhibited by kojic acid and A. flavus DCM extracts with IC₅₀ values of 15.1 and 12.6 µg/mL, respectively. From the spectroscopic analysis, the main anti-tyrosinase compounds of A. flavus extract was resolved, and verified as undecanoic acid. Further studies are ongoing to unravel the in vivo effect and cytotoxicity of this compound in fungi and human, that could be a novel drug to various diseases associated with hyperpigmentation by melanin. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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17 pages, 4085 KiB

Open AccessArticle

Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study

by Maywan Hariono, Rollando Rollando, Jasson Karamoy, Pandu Hariyono, M. Atmono, Maria Djohan, Wiwy Wiwy, Rina Nuwarda, Christopher Kurniawan, Nurul Salin and Habibah Wahab

Molecules 2020, 25(20), 4691; https://doi.org/10.3390/molecules25204691 - 14 Oct 2020

Cited by 22 | Viewed by 4377

Abstract

Matrix metalloproteinase9 (MMP9) is known to be highly expressed during metastatic cancer where most known potential inhibitors failed in the clinical trials. This study aims to select local plants in our state, as anti-breast cancer agent with hemopexin-like domain of MMP9 (PEX9) as the selective protein target. In silico screening for PEX9 inhibitors was performed from our in house-natural compound database to identify the plants. The selected plants were extracted using methanol and then a step-by-step in vitro screening against MMP9 was performed from its crude extract, partitions until fractions using FRET-based assay. The partitions were obtained by performing liquid–liquid extraction on the methanol extract using n-hexane, ethylacetate, n-butanol, and water representing nonpolar to polar solvents. The fractions were made from the selected partition, which demonstrated the best inhibition percentage toward MMP9, using column chromatography. Of the 200 compounds screened, 20 compounds that scored the binding affinity −11.2 to −8.1 kcal/mol toward PEX9 were selected as top hits. The binding of these hits were thoroughly investigated and linked to the plants which they were reported to be isolated from. Six of the eight crude extracts demonstrated inhibition toward MMP9 with the IC₅₀ 24 to 823 µg/mL. The partitions (1 mg/mL) of Ageratum conyzoides aerial parts and Ixora coccinea leaves showed inhibition 94% and 96%, whereas their fractions showed IC₅₀ 43 and 116 µg/mL, respectively toward MMP9. Using MTT assay, the crude extract of Ageratum exhibited IC₅₀ 22 and 229 µg/mL against 4T1 and T47D cell proliferations, respectively with a high safety index concluding its potential anti-breast cancer from herbal. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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33 pages, 9362 KiB

Open AccessFeature PaperEditor’s ChoiceReview

HDAC Inhibitors: Innovative Strategies for Their Design and Applications

by Mateusz Daśko, Beatriz de Pascual-Teresa, Irene Ortín and Ana Ramos

Molecules 2022, 27(3), 715; https://doi.org/10.3390/molecules27030715 - 21 Jan 2022

Cited by 39 | Viewed by 7053

Abstract

Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands). Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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16 pages, 4094 KiB

Open AccessReview

Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives

by Lidia Ciccone, Chiara Cerri, Susanna Nencetti and Elisabetta Orlandini

Molecules 2021, 26(21), 6380; https://doi.org/10.3390/molecules26216380 - 22 Oct 2021

Cited by 43 | Viewed by 6733

Abstract

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO₂/HCO₃. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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39 pages, 12201 KiB

Open AccessReview

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

by Anton Frühauf and Franz-Josef Meyer-Almes

Molecules 2021, 26(17), 5151; https://doi.org/10.3390/molecules26175151 - 25 Aug 2021

Cited by 23 | Viewed by 5919

Abstract

Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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37 pages, 3046 KiB

Open AccessReview

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

by Matteo Calligaris, Doretta Cuffaro, Simone Bonelli, Donatella Pia Spanò, Armando Rossello, Elisa Nuti and Simone Dario Scilabra

Molecules 2021, 26(4), 944; https://doi.org/10.3390/molecules26040944 - 10 Feb 2021

Cited by 65 | Viewed by 8049

Abstract

For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)

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