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Enzymes as Targets for Drug Development II

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 33684

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Prof. Dr. Sung-Kun (Sean) Kim

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Department of Natural Sciences, Northeastern State University, Broken Arrow, OK 74014, USA
Interests: biochemistry; enzymology; drug discovery; SELEX (systematic evolution of ligands by exponential enrichment); in vitro selection technique
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The most attractive targets for drug development are considered enzymes in the pharmaceutical community. Characterization of enzymes is, therefore, critical in understanding their reactions. Many analytical methods are needed to complete characterization such as purification, kinetics, protein stabilization, optimal conditions for pH, temperature, and ionic strength, subtract or product binding, ligand/inhibitor/protein interactions, three-dimensional structure, and conformational changes. Recently, in silico analysis has made a huge contribution to the enzyme characterization. Molecular docking and molecular dynamics should be included as major techniques. This Special Issue brings together a large number of intriguing subjects to promote ideas on enzymes as targets for drug development.

It is envisioned that the following topics would be included in the Special Issue.

Improvement of enzyme purification;

Development of novel inhibitors;

Investigation of enzyme mechanism;

Understanding enzyme conformation changes.

Prof. Dr. Sung-Kun (Sean) Kim
Guest Editor

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Keywords

enzyme kinetics
enzyme-ligand or protein-protein interactions
enzyme inhibitions
enzyme purifications and optimal conditions
enzyme structures
enzyme computational analysis

Published Papers (11 papers)

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Editorial

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4 pages, 455 KiB

Open AccessEditorial

Enzymes as Targets for Drug Development II

by Sung-Kun Kim

Int. J. Mol. Sci. 2023, 24(4), 3258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043258 - 07 Feb 2023

Viewed by 1239

Abstract

Enzymes are viewed as the most desirable targets for drug development by the pharmaceutical community [...] Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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Research

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11 pages, 2580 KiB

Open AccessArticle

Development of Hydroxamic Acid Compounds for Inhibition of Metallo-β-Lactamase from Bacillus anthracis

by Andrew E. Huckleby, Jhawn G. Saul, Hyunshun Shin, Staci Desmarais, Apparao Bokka, Junha Jeon and Sung-Kun Kim

Int. J. Mol. Sci. 2022, 23(16), 9163; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169163 - 15 Aug 2022

Cited by 2 | Viewed by 1390

Abstract

The emergence of resistant bacteria takes place, endangering the effectiveness of antibiotics. A reason for antibiotic resistance is the presence of lactamases that catalyze the hydrolysis of β-lactam antibiotics. An inhibitor of serine-β-lactamases such as clavulanic acid binds to the active site of the enzymes, thus solving the resistance problem. A pressing issue, however, is that the reaction mechanism of metallo-β-lactamases (MBLs) hydrolyzing β-lactam antibiotics differs from that of serine-β-lactamases due to the existence of zinc ions in the active site of MBLs. Thus, the development of potential inhibitors for MBLs remains urgent. Here, the ability to inhibit MBL from Bacillus anthracis (Bla2) was investigated in silico and in vitro using compounds possessing two hydroxamate functional groups such as 3-chloro-N-hydroxy-4-(7-(hydroxyamino)-7-oxoheptyl)benzamide (Compound 4) and N-hydroxy-4-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxybenzamide (Compound 6). In silico docking and molecular dynamics simulations revealed that both Compounds 4 and 6 were coordinated with zinc ions in the active site, suggesting that the hydroxamate group attached to the aromatic ring of the compound plays a crucial role in the coordination to the zinc ions. In vitro kinetic analysis demonstrated that the mode of inhibitions for Compounds 4 and 6 were a competitive inhibition with Ki values of 6.4 ± 1.7 and 4.7 ± 1.4 kcal/mol, respectively. The agreement between in silico and in vitro investigations indicates that compounds containing dihyroxamate moieties may offer a new avenue to overcome antibiotic resistance to bacteria. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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17 pages, 7076 KiB

Open AccessArticle

Catalase Inhibition by Aminoalkanol Derivatives with Potential Anti-Cancer Activity—In Vitro and In Silico Studies Using Capillary Electrophoresis Method

by Błażej Grodner, Mariola Napiórkowska and Dariusz Maciej Pisklak

Int. J. Mol. Sci. 2022, 23(13), 7123; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137123 - 27 Jun 2022

Cited by 2 | Viewed by 1644

Abstract

In this work, the investigation of type and inhibitory strength of catalase by two pairs of aminoalkanol derivatives (1,7 diEthyl- and 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene- 3,5,10-trione) has been presented. The obtained results allowed for the determination of all kinetic parameters (Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC₅₀) on the basis of which it was shown that all four aminoalkanol derivatives are competitive inhibitors of catalase. However, the strength of action of each of them depends on the type of substituents present in the main structure of the molecule. Subtle differences in the potency of individual derivatives were possible to detect thanks to the developed, sensitive method of capillary electrophoresis, which allowed simultaneous monitoring of the mutual changes in the concentrations of substrates and products of the reaction catalyzed by the enzyme. Detailed values of kinetic parameters showed that all derivatives are weak inhibitors of catalase, which in this case is a big advantage because each inhibition of catalase activity is associated with a greater amount of accumulated, harmful reactive oxygen species. The results of docking studies also show the convergence of the binding energies values of individual inhibitors with all kinetic parameters of the investigated catalase inhibition and thus additionally confirm the weak inhibitory strength of all four aminoalkanol derivatives. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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20 pages, 9248 KiB

Open AccessArticle

Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives

by Rongxing Liu, Cécile Mathieu, Jérémy Berthelet, Wenchao Zhang, Jean-Marie Dupret and Fernando Rodrigues Lima

Int. J. Mol. Sci. 2022, 23(13), 7027; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137027 - 24 Jun 2022

Cited by 30 | Viewed by 4440

Abstract

Phosphorylation is an essential process in biological events and is considered critical for biological functions. In tissues, protein phosphorylation mainly occurs on tyrosine (Tyr), serine (Ser) and threonine (Thr) residues. The balance between phosphorylation and dephosphorylation is under the control of two super enzyme families, protein kinases (PKs) and protein phosphatases (PPs), respectively. Although there are many selective and effective drugs targeting phosphokinases, developing drugs targeting phosphatases is challenging. PTP1B, one of the most central protein tyrosine phosphatases (PTPs), is a key player in several human diseases and disorders, such as diabetes, obesity, and hematopoietic malignancies, through modulation of different signaling pathways. However, due to high conservation among PTPs, most PTP1B inhibitors lack specificity, raising the need to develop new strategies targeting this enzyme. In this mini-review, we summarize three classes of PTP1B inhibitors with different mechanisms: (1) targeting multiple aryl-phosphorylation sites including the catalytic site of PTP1B; (2) targeting allosteric sites of PTP1B; (3) targeting specific mRNA sequence of PTP1B. All three types of PTP1B inhibitors present good specificity over other PTPs and are promising for the development of efficient small molecules targeting this enzyme. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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16 pages, 3299 KiB

Open AccessArticle

Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes

by Charoutioun S. Bodourian, Nirmal Poudel, Anastassios C. Papageorgiou, Mariana Antoniadi, Nikolaos D. Georgakis, Hiroshi Abe and Nikolaos E. Labrou

Int. J. Mol. Sci. 2022, 23(7), 3606; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073606 - 25 Mar 2022

Cited by 2 | Viewed by 1932

Abstract

Glutathione transferases (GSTs; EC 2.5.1.18) form a group of multifunctional enzymes that are involved in phase II of the cellular detoxification mechanism and are associated with increased susceptibility to cancer development and resistance to anticancer drugs. The present study aims to evaluate the ligandability of the human GSTM1-1 isoenzyme (hGSTM1-1) using a broad range of structurally diverse pesticides as probes. The results revealed that hGSTM1-1, compared to other classes of GSTs, displays limited ligandability and ligand-binding promiscuity, as revealed by kinetic inhibition studies. Among all tested pesticides, the carbamate insecticide pirimicarb was identified as the strongest inhibitor towards hGSTM1-1. Kinetic inhibition analysis showed that pirimicarb behaved as a mixed-type inhibitor toward glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). To shine a light on the restricted hGSTM1-1 ligand-binding promiscuity, the ligand-free crystal structure of hGSTM1-1 was determined by X-ray crystallography at 1.59 Å-resolution. Comparative analysis of ligand-free structure with the available ligand-bound structures allowed for the study of the enzyme’s plasticity and the induced-fit mechanism operated by hGSTM1-1. The results revealed important structural features of the H-site that contribute to xenobiotic-ligand binding and specificity. It was concluded that hGSTM1-1 interacts preferentially with one-ring aromatic compounds that bind at a discrete site which partially overlaps with the xenobiotic substrate binding site (H-site). The results of the study form a basis for the rational design of new drugs targeting hGSTM1-1. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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18 pages, 5685 KiB

Open AccessArticle

The Family Keeps on Growing: Four Novel Fungal OYEs Characterized

by Marina Simona Robescu, Giovanni Loprete, Matteo Gasparotto, Filippo Vascon, Francesco Filippini, Laura Cendron and Elisabetta Bergantino

Int. J. Mol. Sci. 2022, 23(6), 3050; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063050 - 11 Mar 2022

Cited by 4 | Viewed by 2104

Abstract

Aiming at expanding the portfolio of Old Yellow Enzymes (OYEs), which have been systematically studied to be employed in the chemical and pharmaceutical industries as useful biocatalysts, we decided to explore the immense reservoir of filamentous fungi. We drew from the genome of the two Ascomycetes Aspergillus niger and Botryotinia fuckeliana four new members of the OYE superfamily belonging to the classical and thermophilic-like subfamilies. The two BfOYEs show wider substrate spectra than the AnOYE homologues, which appear as more specialized biocatalysts. According to their mesophilic origins, the new enzymes neither show high thermostability nor extreme pH optimums. The crystal structures of BfOYE4 and AnOYE8 have been determined, revealing the conserved features of the thermophilic-like subclass as well as unique properties, such as a peculiar N-terminal loop involved in dimer surface interactions. For the classical representatives BfOYE1 and AnOYE2, model structures were built and analyzed, showing surprisingly wide open access to the active site cavities due to a shorter β6-loop and a disordered capping subdomain. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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19 pages, 5874 KiB

Open AccessArticle

In Vitro and In Silico Kinetic Studies of Patented 1,7-diEthyl and 1,7-diMethyl Aminoalkanol Derivatives as New Inhibitors of Acetylcholinesterase

by Błażej Grodner, Mariola Napiórkowska and Dariusz Maciej Pisklak

Int. J. Mol. Sci. 2022, 23(1), 270; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010270 - 27 Dec 2021

Cited by 3 | Viewed by 2080

Abstract

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC₅₀ values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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16 pages, 2872 KiB

Open AccessArticle

Kinetic Studies of Newly Patented Aminoalkanol Derivatives with Potential Anticancer Activity as Competitive Inhibitors of Prostate Acid Phosphatase

by Błażej Grodner, Mariola Napiórkowska and Dariusz Maciej Pisklak

Int. J. Mol. Sci. 2021, 22(21), 11761; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111761 - 29 Oct 2021

Cited by 4 | Viewed by 1721

Abstract

Background: Acid phosphatase and its regulation are important objects of biological and clinical research and play an important role in the development and treatment of prostate and bone diseases. The newly patented aminoalkanol (4-[2-hydroxy-3-(propan-2-ylamino)propyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (I) and (4-[3-(dimethylamino)-2-hydroxypropyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (II) derivatives have potential anticancer activity, and their influence on enzymatic activity can significantly impact the therapeutic effects of acid phosphatase against many diseases. Therefore, in this study, we investigated the action of compounds (I) and (II) on acid phosphatase. Methods: Capillary electrophoresis was used to evaluate the inhibition of acid phosphatase. Lineweaver–Burk plots were constructed to compare the Km of this enzyme in the presence of inhibitors (I) or (II) with the Km in solutions without these inhibitors. Results: Compound (I) showed a stronger competitive inhibition against acid phosphatase, whereas derivative (II) showed a weaker competitive type of inhibition. The detailed kinetic studies of these compounds showed that their type and strength of inhibition as well as affinity depend on the kind of substituent occurring in the main chemical molecule. Conclusions: This study is of great importance because the disclosed inhibition of acid phosphatase by compounds (I) and (II) raises the question of whether these compounds could have any effect on the treatment possibilities of prostate diseases. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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22 pages, 5694 KiB

Open AccessArticle

The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study

by Angela Parise, Isabella Romeo, Nino Russo and Tiziana Marino

Int. J. Mol. Sci. 2021, 22(18), 9792; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189792 - 10 Sep 2021

Cited by 10 | Viewed by 3337

Abstract

The inhibition mechanism of the main protease (M^pro) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of M^pro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se–S covalent bond mediated by EBS and EBS-OH on M^pro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of M^pro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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16 pages, 5778 KiB

Open AccessArticle

The Oxoglutarate Binding Site and Regulatory Mechanism Are Conserved in Ammonium Transporter Inhibitors GlnKs from Methanococcales

by Marie-Caroline Müller and Tristan Wagner

Int. J. Mol. Sci. 2021, 22(16), 8631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168631 - 11 Aug 2021

Cited by 4 | Viewed by 1779

Abstract

Protein inhibition is a natural regulatory process to control cellular metabolic fluxes. P_II-family signal-transducing effectors are in this matter key regulators of the nitrogen metabolism. Their interaction with their various targets is governed by the cellular nitrogen level and the energy charge. Structural studies on GlnK, a P_II-family inhibitor of the ammonium transporters (Amt), showed that the T-loops responsible for channel obstruction are displaced upon the binding of 2-oxoglutarate, magnesium and ATP in a conserved cleft. However, GlnK from Methanocaldococcus jannaschii was shown to bind 2-oxoglutarate on the tip of its T-loop, causing a moderate disruption to GlnK–Amt interaction, raising the question if methanogenic archaea use a singular adaptive strategy. Here we show that membrane fractions of Methanothermococcus thermolithotrophicus released GlnKs only in the presence of Mg-ATP and 2-oxoglutarate. This observation led us to structurally characterize the two GlnK isoforms apo or in complex with ligands. Together, our results show that the 2-oxoglutarate binding interface is conserved in GlnKs from Methanococcales, including Methanocaldococcus jannaschii, emphasizing the importance of a free carboxy-terminal group to facilitate ligand binding and to provoke the shift of the T-loop positions. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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Review

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34 pages, 9519 KiB

Open AccessReview

Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

by Luping Pang, Stephen D. Weeks and Arthur Van Aerschot

Int. J. Mol. Sci. 2021, 22(4), 1750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041750 - 10 Feb 2021

Cited by 37 | Viewed by 9830

Abstract

Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets. Full article

(This article belongs to the Special Issue Enzymes as Targets for Drug Development II)

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