Jamshed Iqbal
Claus Jacob
Jean Sévigny- 1Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad, Pakistan
- 2Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland, Saarbruecken, Germany
- 3Centre de Recherche du CHU de Québec - Université Laval, Québec City, QC, Canada
- 4Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada
Editorial on the Research Topic
Metalloenzymes: Potential Drug Targets
Metalloenzymes have an important role in the regulation of many biological functions. Overexpressed and/or reduced secretion of such enzymes lead to different complications of clinical interest. The metal ions present in enzymes control the structure, folding, and functions of such proteins. The protein data bank (PDB) revealed that over 50% of proteins contain metal ions (Solomon et al., 1996). The development of metalloenzyme inhibitors are of interest in the treatment of various diseases. The interaction of ligands, i.e., compounds as inhibitors with target proteins via active sites provide a means of curing diseases. Most aptly, the inhibitors reported by academic or pharmaceutical usage of small molecules as inhibitors provide a rapid and viable way to treat diseases. Urease is a ubiquitous metalloenzyme, produced by various cell types from plants, fungi, and bacteria, etc., that bears a nickel atom in its active pocket. It hydrolyzes the urea into ammonia and carbamate which further decompose to ammonia and CO2. The overexpression of urease was known to be linked with ulcers, hepatic coma, and formation of urinary stones (Upadhyay, 2012; Kappaun et al., 2018).
Carbonic anhydrase with zinc metal ion catalyze the hydration of CO2 with water to produce hydrogen carbonate and H+ ions (Alvarez-Leefmans and Delpire, 2009). The hydration reaction involves the nucleophilic attack of the metal-bounded hydroxy (OH) group with the carbon (C) atom of carbon dioxide species (Silverman and Lindskog, 1988). The coordination of carbonic anhydrases (CAs) with metal ion occurs at active sites via binding with histidine, cysteine, and/or glutamine residues to form a tetrahedral shape (Steiner et al., 1975). The inhibitors of CAs have been employed as diuretic and antiglaucoma agents as well as anti-obesity and anticancer agents (Supuran, 2008).
Furthermore, ubiquitous ecto-nucleotidases such as 1) nucleoside triphosphate diphosphohydrolases (NTPDases), 2) nucleotide pyrophosphatase/phosphodiesterases (NPPs), 3) alkaline phosphatases (APs or ALPs), and 4) ecto-5′-nucleotidase (e5′NT) are all responsible for the integrity of proper cell functioning (Supuran, 2008). The NPPs possess zinc (Zn2+) metal ion at active sites while the e5′NT has additionally magnesium ion (Mg2+) at the active site. The overexpression of surface-located ecto-enzymes hydrolyzing nucleotides causes various complications which affect different functions such as cell proliferation, apoptosis as well as degenerative, neurological, and immunological responses. In the current issue, Baqi et al. reported the use of anthraquinone derivatives as NTPDase inhibitors which showed selectivity towards NTPDase2 and -3. The compound, 1-amino-4-(9-phenanthrylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, with an IC50 value of 539 nM was found to be a potent inhibitor of NTPDase2, while the anthraquinone, 1-amino-4-[3-(4,6-dichlorotriazin-2-ylamino)-4-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, showed potency and selectivity towards NTPDase3 with an IC50 of 390 nM. The most potent compounds could serve as front-runners in the goal of treating different pathological complications (Baqi et al.). The inhibitors of NTPDase1 may serve as potential leads in cancer therapy. Adenosine derivatives were screened for CD39 and CD73. The biological assay results showed selective CD39 and dual CD39/CD73 inhibitors (Schäkel et al.). A docking study further showed putative binding of nucleotide analogs with target enzymes. Thus, the inhibition of metalloenzymes might be useful to cure different clinically important complications.
Prof. Iqbal’s research group have made significant progress in the development and identification of different compounds as inhibitors of metalloenzymes. They have reported several inhibitors of carbonic anhydrase activity such as sulfonamides, sulfonates, and sulfamate derivatives (Zaraei et al., 2019; Saeed et al., 2021). Furthermore, many other types of molecules have also been reported as carbonic anhydrase inhibitors (Al-Rashida et al., 2014; Saeed et al., 2014; Zaib et al., 2014; Al-Rashida et al., 2015; Saeed et al., 2017; Abbas et al., 2018; Abbas A. et al., 2019). Supuran (2008) published an excellent review in Nature Review Drug Discovery to present carbonic anhydrase and its inhibitors. The presence of zinc metal provides a means of binding enzymes with several classes of compounds including sulphonamides, sulphamates, and sulphamides.
Urease is also a common target for treating ulcers which possesses two nickel atoms in its core structure. The inhibition of urease has been reported by using different heterocycles. In their studies, Iqbal et al. have reported 1,3-thiazoles (Channar et al., 2021), benzohydrazide derivatives (Abbas S. et al., 2019), acridine-based (thio)semicarbazones, hydrazones (Isaac et al., 2019), and semicarbazones derivatives (Qazi et al., 2018) as urease inhibitors. The copper metal ion containing tyrosinase has been known to be involved in melanin biosynthesis. Lavinda et al. developed a 3D model of the structure of human tyrosinase and TYRP2 on the basis of their crystallographic structure. The mechanism of mercury chloride (HgCl2)-induced tyrosinase inactivation was investigated in this study (Chen et al.).
Iqbal et al. have also made progress on the inhibition of other biological targets which include other ecto-nucleotidases. Various types of heterocyclic scaffolds such as the inhibitors of nucleotide pyrophosphatase/phosphodiesterases (NPPs) include substituted trifluoromethyl quinoline (Semreen et al., 2019), arylated thiadiazolopyrimidones (Jafari et al., 2016), and p-nitrophenyl thymidine 5- monophosphate (Raza et al., 2011). Moreover, the development of ecto-5′-nucleotidase inhibitors may also serve to treat cancer (Iqbal et al., 2013). The heterocyclic compounds which have been synthesized and screened as NTPDases include oxoindolin phenylhydrazine carboxamides (Afzal et al., 2021), pyrrolo[2,3-b]pyridine derivatives (Ullah et al., 2021), spirooxindole derivatives (Ashraf et al., 2020), sulfonylhydrazones (Younus et al., 2020), 2-substituted-7-trifluoromethyl-thiadiazolopyrimidones (Afzal et al., 2020), pyrazolyl pyrimidinetrione, and thioxopyrimidinedione conjugates as selective inhibitors of human ectonucleotidase (Andleeb et al., 2019), etc. Furthermore, the review articles of Iqbal (Iqbal, 2019) have also reported the importance of ectonucleotidase inhibitors in the treatment of various diseases. Though there are many other metal ions-containing proteins which have been targeted to treat clinically relevant conditions, Iqbal et al. have made a significant scientific contribution in finding good choices in the inhibition of urease, carbonic anhydrase, and ectonucleotidases.
In summary, metalloproteins present relevant targets for the development of modulators in order to treat various types of diseases. In this view, development of metalloprotein inhibitors with different structures, such as heterocyclic compounds, provide an excellent opportunity to treat such diseases. The presence of metal ions in these proteins help them bind with the inhibitor and play an important role in the inhibition process. Libraries of small heterocyclic molecules can be readily prepared to screen them against various target proteins to cure corresponding diseases.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Abbas, A., Ali, B., Kanwal, K. M., Khan, K. M., Iqbal, J., Ur Rahman, S., et al. (2019a). Synthesis and In Vitro Urease Inhibitory Activity of Benzohydrazide Derivatives, In Silico and Kinetic Studies. Bioorg. Chem. 82, 163–177. doi:10.1016/j.bioorg.2018.09.036
Abbas, S., Zaib, S., Rahman, S. U., Ali, S., Hameed, S., Tahir, M. N., et al. (2019b). Carbonic Anhydrase Inhibitory Potential of 1,2,4-Triazole-3-Thione Derivatives of Flurbiprofen, Ibuprofen and 4-Tert-Butylbenzoic Hydrazide: Design, Synthesis, Characterization, Biochemical Evaluation, Molecular Docking and Dynamic Simulation Studies. Med. Chem. 15 (3), 298–310. doi:10.2174/1573406414666181012165156
Abbas, S., Nasir, H. H., Zaib, S., Ali, S., Mahmood, T., Ayub, K., et al. (2018). Carbonic Anhydrase Inhibition of Schiff Base Derivative of Imino-Methyl-Naphthalen-2-Ol: Synthesis, Structure Elucidation, Molecular Docking, Dynamic Simulation and Density Functional Theory Calculations. J. Mol. Struct. 1156, 193–200. doi:10.1016/j.molstruc.2017.11.086
Afzal, S., Al-Rashida, M., Hameed, A., Pelletier, J., Sévigny, J., and Iqbal, J. (2021). Synthesis, In-Vitro Evaluation and Molecular Docking Studies of Oxoindolin Phenylhydrazine Carboxamides as Potent and Selective Inhibitors of Ectonucleoside Triphosphate Diphosphohydrolase (NTPDase). Bioorg. Chem. 112, 104957. doi:10.1016/j.bioorg.2021.104957
Afzal, S., Zaib, S., Jafari, B., Langer, P., Lecka, J., Sévigny, J., et al. (2020). Highly Potent and Selective Ectonucleoside Triphosphate Diphosphohydrolase (ENTPDase1, 2, 3 and 8) Inhibitors Having 2-substituted-7- Trifluoromethyl-Thiadiazolopyrimidones Scaffold. Med. Chem. 16 (5), 689–702. doi:10.2174/1573406415666190614095821
Al-Rashida, M., Ejaz, S. A., Ali, S., Shaukat, A., Hamayoun, M., Ahmed, M., et al. (2015). Diarylsulfonamides and Their Bioisosteres as Dual Inhibitors of Alkaline Phosphatase and Carbonic Anhydrase: Structure Activity Relationship and Molecular Modelling Studies. Bioorg. Med. Chem. 23 (10), 2435–2444. doi:10.1016/j.bmc.2015.03.054
Al-Rashida, M., Hussain, S., Hamayoun, M., Altaf, A., and Iqbal, J. (2014). Sulfa Drugs as Inhibitors of Carbonic Anhydrase: New Targets for the Old Drugs. Biomed. Res. Int. 2014, 162928. doi:10.1155/2014/162928
Alvarez-Leefmans, F. J., and Delpire, E. (2009). Physiology and Pathology of Chloride Transporters and Channels in the Nervous System: From Molecules to Diseases. Academic Press.
Andleeb, H., Hameed, S., Ejaz, S. A., Khan, I., Zaib, S., Lecka, J., et al. (2019). Probing the High Potency of Pyrazolyl Pyrimidinetriones and Thioxopyrimidinediones as Selective and Efficient Non-nucleotide Inhibitors of Recombinant Human Ectonucleotidases. Bioorg. Chem. 88, 102893. doi:10.1016/j.bioorg.2019.03.067
Ashraf, A., Shafiq, Z., Khan Jadoon, M. S., Tahir, M. N., Pelletier, J., Sevigny, J., et al. (2020). Synthesis, Characterization, and In Silico Studies of Novel Spirooxindole Derivatives as Ecto-5'-Nucleotidase Inhibitors. ACS Med. Chem. Lett. 11 (12), 2397–2405. doi:10.1021/acsmedchemlett.0c00343
Channar, P. A., Saeed, A., Afzal, S., Hussain, D., Kalesse, M., Shehzadi, S. A., et al. (2021). Hydrazine Clubbed 1,3-thiazoles as Potent Urease Inhibitors: Design, Synthesis and Molecular Docking Studies. Mol. Divers. 25 (2), 1–13. doi:10.1007/s11030-020-10057-7
Iqbal, J., Saeed, A., Raza, R., Matin, A., Hameed, A., Furtmann, N., et al. (2013). Identification of Sulfonic Acids as Efficient Ecto-5'-Nucleotidase Inhibitors. Eur. J. Med. Chem. 70, 685–691. doi:10.1016/j.ejmech.2013.10.053
Iqbal, J. (2019). Ectonucleotidases: Potential Target in Drug Discovery and Development. Mrmc 19 (11), 866–869. doi:10.2174/138955751911190517102116
Isaac, I. O., Al-Rashida, M., Rahman, S. U., Alharthy, R. D., Asari, A., Hameed, A., et al. (2019). Acridine-based (Thio)semicarbazones and Hydrazones: Synthesis, In Vitro Urease Inhibition, Molecular Docking and In-Silico ADME Evaluation. Bioorg. Chem. 82, 6–16. doi:10.1016/j.bioorg.2018.09.032
Jafari, B., Yelibayeva, N., Ospanov, M., Ejaz, S. A., Afzal, S., Khan, S. U., et al. (2016). Synthesis of 2-arylated Thiadiazolopyrimidones by Suzuki-Miyaura Cross-Coupling: a New Class of Nucleotide Pyrophosphatase (NPPs) Inhibitors. RSC Adv. 6 (109), 107556–107571. doi:10.1039/c6ra22750c
Kappaun, K., Piovesan, A. R., Carlini, C. R., and Ligabue-Braun, R. (2018). Ureases: Historical Aspects, Catalytic, and Non-catalytic Properties - A Review. J. Adv. Res. 13, 3–17. doi:10.1016/j.jare.2018.05.010
Qazi, S. U., Rahman, S. U., Awan, A. N., Al-Rashida, M., Alharthy, R. D., Asari, A., et al. (2018). Semicarbazone Derivatives as Urease Inhibitors: Synthesis, Biological Evaluation, Molecular Docking Studies and In-Silico ADME Evaluation. Bioorg. Chem. 79, 19–26. doi:10.1016/j.bioorg.2018.03.029
Raza, R., Akhtar, T., Hameed, S., Lecka, J., Iqbal, J., and Sevigny, J. (2011). Identification of Potent and Selective Human Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase-3 (hNPP3) Inhibitors. Open Enzyme Inhib. J. 4, 17–22. doi:10.2174/1874940201104010017
Saeed, A., Al-Rashida, M., Hamayoun, M., Mumtaz, A., and Iqbal, J. (2014). Carbonic Anhydrase Inhibition by 1-Aroyl-3-(4-Aminosulfonylphenyl)thioureas. J. Enzyme Inhib. Med. Chem. 29 (6), 901–905. doi:10.3109/14756366.2013.866660
Saeed, A., Khan, S. U., Mahesar, P. A., Channar, P. A., Shabir, G., and Iqbal, J. (2017). Substituted (E)-2-(2-benzylidenehydrazinyl)-4-methylthiazole-5-carboxylates as Dual Inhibitors of 15-lipoxygenase & Carbonic Anhydrase II: Synthesis, Biochemical Evaluation and Docking Studies. Biochem. Biophys. Res. Commun. 482 (1), 176–181. doi:10.1016/j.bbrc.2016.11.028
Saeed, A., Ejaz, S. A., Ul-Hamid, A., El-Seedi, H. R., and Iqbal, J. (2021). Synthesis of and Molecular Docking Studies of Azomethine- Tethered Sulfonamides as Carbonic Anhydrase II & 15-lipoxygenase Inhibitors. J. Mol. Struct. 1243, 130821. doi:10.1016/j.molstruc.2021.130821
Semreen, M. H., El-Gamal, M. I., Ullah, S., Jalil, S., Zaib, S., Anbar, H. S., et al. (2019). Synthesis, Biological Evaluation, and Molecular Docking Study of Sulfonate Derivatives as Nucleotide Pyrophosphatase/phosphodiesterase (NPP) Inhibitors. Bioorg. Med. Chem. 27 (13), 2741–2752. doi:10.1016/j.bmc.2019.04.031
Silverman, D. N., and Lindskog, S. (1988). The Catalytic Mechanism of Carbonic Anhydrase: Implications of a Rate-Limiting Protolysis of Water. Acc. Chem. Res. 21 (1), 30–36. doi:10.1021/ar00145a005
Solomon, E. I., Sundaram, U. M., and Machonkin, T. E. (1996). Multicopper Oxidases and Oxygenases. Chem. Rev. 96 (7), 2563–2606. doi:10.1021/cr950046o
Steiner, H., Jonsson, B. H., and Lindskog, S. (1975). The Catalytic Mechanism of Carbonic Anhydrase. Hydrogen-Isotope Effects on the Kinetic Parameters of the Human C Isoenzyme. Eur. J. Biochem. 59 (1), 253–259. doi:10.1111/j.1432-1033.1975.tb02449.x
Supuran, C. T. (2008). Carbonic Anhydrases: Novel Therapeutic Applications for Inhibitors and Activators. Nat. Rev. Drug Discov. 7 (2), 168–181. doi:10.1038/nrd2467
Ullah, S., El-Gamal, M. I., El-Gamal, R., Pelletier, J., Sévigny, J., Shehata, M. K., et al. (2021). Synthesis, Biological Evaluation, and Docking Studies of Novel Pyrrolo [2, 3-b] Pyridine Derivatives as Both Ectonucleotide Pyrophosphatase/phosphodiesterase Inhibitors and Antiproliferative Agents. Eur. J. Med. Chem. 217, 113339. doi:10.1016/j.ejmech.2021.113339
Younus, H. A., Hameed, A., Mahmood, A., Khan, M. S., Saeed, M., Batool, F., et al. (2020). Sulfonylhydrazones: Design, synthesis and investigation of ectonucleotidase (ALP & e5'NT) inhibition activities. Bioorg. Chem. 100, 103827. doi:10.1016/j.bioorg.2020.103827
Zaib, S., Saeed, A., Stolte, K., Flörke, U., Shahid, M., and Iqbal, J. (2014). New Aminobenzenesulfonamide-Thiourea Conjugates: Synthesis and Carbonic Anhydrase Inhibition and Docking Studies. Eur. J. Med. Chem. 78, 140–150. doi:10.1016/j.ejmech.2014.03.023
Zaraei, S. O., El-Gamal, M. I., Shafique, Z., Amjad, S. T., Afridi, S., Zaib, S., et al. (2019). Sulfonate and Sulfamate Derivatives Possessing Benzofuran or Benzothiophene Nucleus as Potent Carbonic Anhydrase II/IX/XII Inhibitors. Bioorg. Med. Chem. 27 (17), 3889–3901. doi:10.1016/j.bmc.2019.07.026
Keywords: metalloenzymes, ecto-5′-nucleotidase, nucleotide pyrophosphatase/phosphodiesterases, nucleoside triphosphate diphosphohydrolases, inhibitors
Citation: Iqbal J, Jacob C and Sévigny J (2021) Editorial: Metalloenzymes: Potential Drug Targets. Front. Pharmacol. 12:746925. doi: 10.3389/fphar.2021.746925
Received: 25 July 2021; Accepted: 07 September 2021;
Published: 24 September 2021.
Edited and reviewed by:
Salvatore Salomone, University of Catania, ItalyCopyright © 2021 Iqbal, Jacob and Sévigny. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jamshed Iqbal, drjamshed@cuiatd.edu.pk