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Biomolecules
Special Issues
Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier
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Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 20691

Special Issue Editors

Dr. Sherif T. S. Hassan

E-Mail Website
Guest Editor
Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic
Interests: infectious diseases; herpesviruses; pharmacology and toxicology; molecular medicine; oncology and hematology; cardiovascular diseases; natural products; drug discovery; analytical and bioanalytical techniques
Special Issues, Collections and Topics in MDPI journals
Dr. Seyed Mohammad Nabavi

E-Mail Website
Guest Editor
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Interests: molecular pharmacology; natural products

Special Issue Information

Dear Colleagues,

In recent years, strucural and mechanistic enzymology played a central role in current drug discovery research and development. This is due to the important role of enzymes as a drug targets. Over the past few decades, small-molecule enzyme inhibitors as enzyme-targeted drugs have shown to exert remarked therapeutic and commercial success in current drug discovery and development. As a successful example, kinase inhibitors and their critical role in cancer biology. Given the importance of enzymes as drug targets, it’s crucial to understand the course of an enzyme-catalyzed reaction along with enzyme structure, which in turn, will aid to conceptualize and design different types of potent inhibitors with various mechanisms of action required for drug efficiency.

This Special Issue aims to shed light on the latest progress in structural and mechanistic enzymology research in drug discovery. Special focus will be paid for enzyme inhibitors and their mechanisms of action along with their application in clinical practice for the treatment of various diseases.

We encourage submissions of original research articles (preclinical and clinical studies), reviews, methods article, perspectives, technology report, opinions, and commentaries that make a novel and substantial contribution to the scientific community.

Dr. Sherif T. S. Hassan
Dr. Seyed Mohammad Nabavi
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 submissions that pass pre-check are 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. Biomolecules 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 2700 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

  • Mechanistic enzymology
  • Enzyme inhibitors
  • Drug Targets
  • Enzyme-catalyzed reaction
  • Enzyme-ligand interaction
  • Drug Discovery
  • 3D crystal structure of enzymes
  • Isolation, purification and expression of enzymes

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Published Papers (5 papers)

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Research

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9 pages, 1062 KiB  
Article
Inhibition of Human Cathepsins B and L by Caffeic Acid and Its Derivatives
by Liza Ulčakar and Marko Novinec
Biomolecules 2021, 11(1), 31; https://doi.org/10.3390/biom11010031 - 29 Dec 2020
Cited by 5 | Viewed by 3159
Abstract
Caffeic acid (CA) and its derivatives caffeic acid phenethyl ester (CAPE) and chlorogenic acid (CGA) are phenolic compounds of plant origin with a wide range of biological activities. Here, we identify and characterize their inhibitory properties against human cathepsins B and L, potent, [...] Read more.
Caffeic acid (CA) and its derivatives caffeic acid phenethyl ester (CAPE) and chlorogenic acid (CGA) are phenolic compounds of plant origin with a wide range of biological activities. Here, we identify and characterize their inhibitory properties against human cathepsins B and L, potent, ubiquitously expressed cysteine peptidases involved in protein turnover and homeostasis, as well as pathological conditions, such as cancer. We show that CAPE and CGA inhibit both peptidases, while CA shows a preference for cathepsin B, resulting in the strongest inhibition among these combinations. All compounds are linear (complete) inhibitors acting via mixed or catalytic mechanisms. Cathepsin B is more strongly inhibited at pH 7.4 than at 5.5, and CA inhibits its endopeptidase activity preferentially over its peptidyl-dipeptidase activity. Altogether, the results identify the CA scaffold as a promising candidate for the development of cathepsin B inhibitors, specifically targeting its endopeptidase activity associated with pathological proteolysis of extracellular substrates. Full article
(This article belongs to the Special Issue Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier)
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20 pages, 2521 KiB  
Article
Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase
by Kamal Adhikari, I-Wen Lo, Chun-Liang Chen, Yung-Lin Wang, Kuan-Hung Lin, Saeid Malek Zadeh, Rajesh Rattinam, Yi-Shan Li, Chang-Jer Wu and Tsung-Lin Li
Biomolecules 2020, 10(5), 738; https://doi.org/10.3390/biom10050738 - 9 May 2020
Cited by 4 | Viewed by 4338
Abstract
Plant type III polyketide synthases produce diverse bioactive molecules with a great medicinal significance to human diseases. Here, we demonstrated versatility of a stilbene synthase (STS) from Pinus Sylvestris, which can accept various non-physiological substrates to form unnatural polyketide products. Three enzymes [...] Read more.
Plant type III polyketide synthases produce diverse bioactive molecules with a great medicinal significance to human diseases. Here, we demonstrated versatility of a stilbene synthase (STS) from Pinus Sylvestris, which can accept various non-physiological substrates to form unnatural polyketide products. Three enzymes (4-coumarate CoA ligase, malonyl-CoA synthetase and engineered benzoate CoA ligase) along with synthetic chemistry was practiced to synthesize starter and extender substrates for STS. Of these, the crystal structures of benzoate CoA ligase (BadA) from Rhodopseudomonas palustris in an apo form or in complex with a 2-chloro-1,3-thiazole-5-carboxyl-AMP or 2-methylthiazole-5-carboxyl-AMP intermediate were determined at resolutions of 1.57 Å, 1.7 Å, and 2.13 Å, respectively, which reinforces its capacity in production of unusual CoA starters. STS exhibits broad substrate promiscuity effectively affording structurally diverse polyketide products. Seven novel products showed desired cytotoxicity against a panel of cancer cell lines (A549, HCT116, Cal27). With the treatment of two selected compounds, the cancer cells underwent cell apoptosis in a dose-dependent manner. The precursor-directed biosynthesis alongside structure-guided enzyme engineering greatly expands the pharmaceutical repertoire of lead compounds with promising/enhanced biological activities. Full article
(This article belongs to the Special Issue Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier)
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13 pages, 973 KiB  
Article
A Multi-Biochemical and In Silico Study on Anti-Enzymatic Actions of Pyroglutamic Acid against PDE-5, ACE, and Urease Using Various Analytical Techniques: Unexplored Pharmacological Properties and Cytotoxicity Evaluation
by Miroslava Šudomová, Sherif T. S. Hassan, Haroon Khan, Mahsa Rasekhian and Seyed Mohammad Nabavi
Biomolecules 2019, 9(9), 392; https://doi.org/10.3390/biom9090392 - 21 Aug 2019
Cited by 24 | Viewed by 4284
Abstract
In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important [...] Read more.
In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important clinical conditions in humans. Radioactivity-based assay, spectrophotometric-based assay, and an Electrospray Ionization-Mass Spectrometry-based method were employed to ascertain the inhibitory actions of pGlu against PDE5A1, ACE, and urease, respectively. The results unveiled that pGlu potently suppressed the activity of PDE5A1 (half-maximal inhibitory concentration; IC50 = 5.23 µM) compared with that of standard drug sildenafil citrate (IC50 = 7.14 µM). Moreover, pGlu at a concentration of 20 µg/mL was found to efficiently inhibit human ACE with 98.2% inhibition compared with that of standard captopril (99.6%; 20 µg/mL). The urease-catalyzed reaction was also remarkably inactivated by pGlu and standard acetohydroxamic acid with IC50 values of 1.8 and 3.9 µM, respectively. Remarkably, the outcome of in vitro cytotoxicity assay did not reveal any significant cytotoxic properties of pGlu against human cervical carcinoma cells and normal human fetal lung fibroblast cells. In addition to in vitro assays, molecular docking analyses were performed to corroborate the outcomes of in vitro results with predicted structure–activity relationships. In conclusion, pGlu could be presented as a natural and multifunctional agent with promising applications in the treatment of some ailments connected with the above-mentioned anti-enzymatic properties. Full article
(This article belongs to the Special Issue Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier)
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12 pages, 651 KiB  
Article
Ziziphora taurica subsp. taurica: Analytical Characterization and Biological Activities
by Michał Tomczyk, Olcay Ceylan, Marcello Locatelli, Angela Tartaglia, Vincenzo Ferrone and Cengiz Sarikurkcu
Biomolecules 2019, 9(8), 367; https://doi.org/10.3390/biom9080367 - 14 Aug 2019
Cited by 7 | Viewed by 3948
Abstract
The Lamiaceae family comprises many flowering plants classified into about 236 genera. The genus Ziziphora is one of the well-known genera of this family and its species are important in different fields of pharmaceutical, chemical, traditional, and folk medicines. The phytochemicals present in [...] Read more.
The Lamiaceae family comprises many flowering plants classified into about 236 genera. The genus Ziziphora is one of the well-known genera of this family and its species are important in different fields of pharmaceutical, chemical, traditional, and folk medicines. The phytochemicals present in Ziziphora include monoterpenic essential oils, triterpenes, and phenolic substances. The aim of this paper was to study the phytochemical profile of Ziziphora taurica subsp. taurica and compare and evaluate the biological activities of its ethyl acetate (ZTT-EtOAc), methanolic (ZTT-MeOH), and aqueous (ZTT-W) extracts based on their enzyme inhibition and antioxidant capacities. Determination of total phenolic (TPC) and total flavonoid (TFC) contents as well as biological activities were determined using spectrophotometric procedures. Subsequently, the individual phenolic compounds were detected by liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS). In total, twenty-two different phenolic compounds were identified, including apigenin, ferulic acid, and luteolin which were the most common. ZTT-MeOH extract showed the best antioxidant activity, whereas ZTT-EtOAc extract was the most effective against tyrosinase and α-amylase. Ziziphora taurica subsp. taurica represents a potential source of natural compounds with positive effects on human health. Full article
(This article belongs to the Special Issue Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier)
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Review

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14 pages, 3124 KiB  
Review
Strained Conformations of Nucleosides in Active Sites of Nucleoside Phosphorylases
by Irina A. Il’icheva, Konstantin M. Polyakov and Sergey N. Mikhailov
Biomolecules 2020, 10(4), 552; https://doi.org/10.3390/biom10040552 - 5 Apr 2020
Cited by 8 | Viewed by 3947
Abstract
Nucleoside phosphorylases catalyze the reversible phosphorolysis of nucleosides to heterocyclic bases, giving α-d-ribose-1-phosphate or α-d-2-deoxyribose-1-phosphate. These enzymes are involved in salvage pathways of nucleoside biosynthesis. The level of these enzymes is often elevated in tumors, which can be used [...] Read more.
Nucleoside phosphorylases catalyze the reversible phosphorolysis of nucleosides to heterocyclic bases, giving α-d-ribose-1-phosphate or α-d-2-deoxyribose-1-phosphate. These enzymes are involved in salvage pathways of nucleoside biosynthesis. The level of these enzymes is often elevated in tumors, which can be used as a marker for cancer diagnosis. This review presents the analysis of conformations of nucleosides and their analogues in complexes with nucleoside phosphorylases of the first (NP-1) family, which includes hexameric and trimeric purine nucleoside phosphorylases (EC 2.4.2.1), hexameric and trimeric 5′-deoxy-5′-methylthioadenosine phosphorylases (EC 2.4.2.28), and uridine phosphorylases (EC 2.4.2.3). Nucleosides adopt similar conformations in complexes, with these conformations being significantly different from those of free nucleosides. In complexes, pentofuranose rings of all nucleosides are at the W region of the pseudorotation cycle that corresponds to the energy barrier to the N↔S interconversion. In most of the complexes, the orientation of the bases with respect to the ribose is in the high-syn region in the immediate vicinity of the barrier to syn ↔ anti transitions. Such conformations of nucleosides in complexes are unfavorable when compared to free nucleosides and they are stabilized by interactions with the enzyme. The sulfate (or phosphate) ion in the active site of the complexes influences the conformation of the furanose ring. The binding of nucleosides in strained conformations is a characteristic feature of the enzyme–substrate complex formation for this enzyme group. Full article
(This article belongs to the Special Issue Structural and Mechanistic Enzymology in Drug Discovery: A New Frontier)
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