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Processes
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Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors
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Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Biological Processes and Systems".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 15932

Special Issue Editors

Prof. Dr. Renata Mikstacka

E-Mail Website
Guest Editor
Department of Inorganic and Analytical Chemistry, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-089 Bydgoszcz, Poland
Interests: medicinal chemistry; enzyme structure and function; anticancer agents
Dr. Zbigniew Dutkiewicz

E-Mail Website
Guest Editor
Department of Chemical Technology of Drugs, Poznań University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
Interests: molecular interactions; computer-aided drug design; anticancer agents
Dr. Marcin Wierzchowski

E-Mail Website
Guest Editor
Department of Chemical Technology of Drugs, Poznań University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
Interests: synthesis of nitroimidazole and trans-stilbene anticancer agents; phototherapy (PDT) and photo diagnostics (PDD); synthesis of new photosensitizers with anticancer, antimicrobial, and antivirus activity

Special Issue Information

Dear Colleagues,

Human metabolism is determined by enzyme functions. For several decades, studies of enzyme expression and activity have been conducted with the use of natural or specially designed and synthesized inhibitors. In the past, the affinity of inhibitors to enzyme binding sites and the mechanism of inhibition were explored mostly as part of kinetic studies. Recently, computational methods such as molecular modeling, docking, and molecular dynamics simulations have been extensively used in research, resulting in substantial progress in our knowledge of enzyme structure and inhibitor-active site interactions. For many enzymes and their isozymes, complex X-ray three-dimensional structures with substrates/inhibitors are available. However, intensive studies are continuing to elucidate intramolecular interactions that influence active site architecture.

This Special Issue, devoted to "Synthesis, Biological Evaluation, and Molecular Modeling of Enzyme Inhibitors," invites high-quality research papers focusing on the structural investigation of enzymes in interaction with substrates/inhibitors. Topics of interest include the following:

  • Design of enzyme inhibitors and prediction of their activity;
  • Structure-activity relationship;
  • Molecular docking and modeling;
  • Screening for active substances.
Prof. Dr. Renata Mikstacka
Dr. Zbigniew Dutkiewicz
Dr. Marcin Wierzchowski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Processes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enzyme inhibitors
  • chemical synthesis
  • biological activities
  • molecular modeling
  • virtual screening
  • drug design

Published Papers (5 papers)

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Research

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18 pages, 2036 KiB  
Article
Gold(I) Complexes with P-Donor Ligands and Their Biological Evaluation
by Monika Richert, Renata Mikstacka, Mariusz Walczyk, Marcin Janusz Cieślak, Julia Kaźmierczak-Barańska, Karolina Królewska-Golińska, Tadeusz Mikołaj Muzioł and Stanisław Biniak
Processes 2021, 9(12), 2100; https://doi.org/10.3390/pr9122100 - 23 Nov 2021
Viewed by 1865
Abstract
Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as [...] Read more.
Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors)
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14 pages, 2953 KiB  
Article
Cloning and Expression of Levansucrase Gene of Bacillus velezensis BM-2 and Enzymatic Synthesis of Levan
by Min Xu, Lixia Zhang, Fangkun Zhao, Jingyue Wang, Bo Zhao, Zhijiang Zhou and Ye Han
Processes 2021, 9(2), 317; https://doi.org/10.3390/pr9020317 - 09 Feb 2021
Cited by 15 | Viewed by 3168
Abstract
Levan is a versatile and valuable fructose homopolymer, and a few bacterial strains have been found to produce levan. Although levan products have numerous specific functions, their application and promotion were limited by the production capacity and production cost. Bacillus velezensis BM-2 is [...] Read more.
Levan is a versatile and valuable fructose homopolymer, and a few bacterial strains have been found to produce levan. Although levan products have numerous specific functions, their application and promotion were limited by the production capacity and production cost. Bacillus velezensis BM-2 is a levan-synthesizing strain, but its levan production is too low to apply. In this study, the levansucrase gene of B. velezensis BM-2 was cloned to plasmid pET-32a-Acma-zz, and the recombinant plasmids were transferred to Escherichia coli BL21. A transformed clone was selected to express and secrete the fusion enzymes with an Acma-tag efficiently. The expressed products were further purified by a self-developed separating material called bacterial enhancer matrix (BEM) particles. The purification efficiency was 93.4%, with a specific activity of 16.589 U/mL protein. The enzymatic reaction results indicated that the optimal reaction temperature is 50 °C, the optimal pH of the acetate buffer is 5.6, and the buffer system greatly influenced the enzyme activity. The enzyme activity was enhanced to 130% in the presence of 5 mM Ca2+, K+, Zn2+, and Mn2+, whereas it was almost abolished in the case of Cu2+ and Fe3+. The values of Km, kcat, and kcat/Km were 17.41 mM, 376.83 s−1, and 21.64 mM−1s−1, respectively. The enzyme amount of 20 U/g sucrose was added to the system containing 400 g/L sucrose, and the levan products with a concentration of 120 g/L reached after an incubation of 18 h, which was 8 times that of the yield before optimization. The results of molecular docking analysis indicated that the Asp86 might act as a nucleophilic catalytic residue for sucrose, Arg246 and Asp247 act as transition state stabilizer of transfructosylation, and Glu340 and Arg306 were recognized as general acid donors. They formed the catalytic-groups triad. The unique properties and catalytic activity of the levansucrase suggest that it deserves further research and might have good industrial application prospects. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors)
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13 pages, 3519 KiB  
Article
Synthesis of 2-(4-hydroxyphenyl)ethyl 3,4,5-Trihydroxybenzoate and Its Inhibitory Effect on Sucrase and Maltase
by Wen-Tai Li, Yu-Hsuan Chuang, Jiahn-Haur Liao and Jung-Feng Hsieh
Processes 2020, 8(12), 1603; https://doi.org/10.3390/pr8121603 - 05 Dec 2020
Cited by 1 | Viewed by 1943
Abstract
We report on the synthesis of an active component, 2-(4-hydroxyphenyl)ethyl 3,4,5-trihydroxybenzoate (HETB), from Rhodiola crenulata. Subsequent analysis revealed that HETB exhibits α-glucosidase inhibitory activities on maltase and sucrase, with potency exceeding that of the known α-glucosidase inhibitors (voglibose and acarbose). An inhibition [...] Read more.
We report on the synthesis of an active component, 2-(4-hydroxyphenyl)ethyl 3,4,5-trihydroxybenzoate (HETB), from Rhodiola crenulata. Subsequent analysis revealed that HETB exhibits α-glucosidase inhibitory activities on maltase and sucrase, with potency exceeding that of the known α-glucosidase inhibitors (voglibose and acarbose). An inhibition kinetics study revealed that HETB, acarbose, and voglibose bind to maltase and sucrase, and HETB was shown to be a strong competitive inhibitor of maltase and sucrase. In a molecular docking study based on the crystal structure of α-glucosidase from Saccharomyces cerevisiae, we revealed the HETB binding in the active site of maltase via hydrogen-bond interactions with five amino acid residues: Ser 240, Asp 242, Glu 277, Arg 315, and Asn 350. For HETB docked to the sucrase active site, seven hydrogen bonds (with Asn 114, Glu 148, Gln 201, Asn 228, Gln 381, Ile 383, and Ser 412) were shown. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors)
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13 pages, 25161 KiB  
Article
Mutational Analysis of the Binding of Alternative Substrates and Inhibitors to the Active Site of Human Glutathione Transferase P1–1
by Abeer Shokeer, Aram Ismail, Usama M. Hegazy, Rüdiger H. Kolm and Bengt Mannervik
Processes 2020, 8(10), 1232; https://doi.org/10.3390/pr8101232 - 01 Oct 2020
Cited by 1 | Viewed by 1924
Abstract
Glutathione transferases (GSTs) are enzymes that play a critical role in cellular detoxication by catalyzing the nucleophilic attack of glutathione on the electrophilic center of a number of xenobiotic compounds, including many therapeutic drugs. Mutations of amino acid residues in the glutathione-binding site [...] Read more.
Glutathione transferases (GSTs) are enzymes that play a critical role in cellular detoxication by catalyzing the nucleophilic attack of glutathione on the electrophilic center of a number of xenobiotic compounds, including many therapeutic drugs. Mutations of amino acid residues in the glutathione-binding site of human glutathione transferase P1–1, namely W39C, K45A, Q52A, Q52K, and Q52E, have been engineered. The recombinant mutant proteins were expressed in Escherichia coli, but only mutants K45A, Q52A, and Q52K showed measurable activity. Steady-state kinetics comparing glutathione with the alternative thiol substrate γ-glutamylcysteine demonstrated the importance of the glycine residue in glutathione for high catalytic efficiency. Inhibition experiments with a set of glutathione analogs structurally related to the therapeutic drugs Telintra and Telcyta enabled determination of binding energies that were contributed by different substituents. The effects of substituting amino acid side chains in the glutathione-binding site of the enzyme on binding the glutathione derivatives and catalysis were evaluated. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors)
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Review

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20 pages, 2871 KiB  
Review
New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies
by Renata Mikstacka and Zbigniew Dutkiewicz
Processes 2021, 9(5), 817; https://doi.org/10.3390/pr9050817 - 08 May 2021
Cited by 12 | Viewed by 6108
Abstract
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role [...] Read more.
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role in the pathogenesis of cardiovascular diseases, hormone-related cancers and is responsible for anti-cancer drug resistance. Inhibition of CYP1B1 activity is considered as an approach in cancer chemoprevention and cancer chemotherapy. CYP1B1 can activate anti-cancer prodrugs in tumor cells which display overexpression of CYP1B1 in comparison to normal cells. CYP1B1 involvement in carcinogenesis and cancer progression encourages investigation of CYP1B1 interactions with its ligands: substrates and inhibitors. Computational methods, with a simulation of molecular dynamics (MD), allow the observation of molecular interactions at the binding site of CYP1B1, which are essential in relation to the enzyme’s functions. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Enzyme Inhibitors)
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