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Recent Trends on Enzymes Inhibitors and Activators in Drug Research

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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 (30 April 2018) | Viewed by 42561

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Special Issue Editor

Prof. Dr. Athina Geronikaki

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Guest Editor

School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
Interests: biologically active heterocycles; thiazole; thiazolidinone; benzothiazole; thiadiazoles with antimicrobial activity; COX/LOX, PTP1b, HIV RT enzyme inhibitors; anti inflammatory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is known that enzymes are involved in many pathological conditions, such as inflammation, diabetes, microbial infections, HIV, and neoplastic diseases among others. Enzyme inhibition is universally accepted as a strategy to treat the above mentioned conditions or to alternate the mechanism involved. Thus, the aim of the current Special Issue is to collect and present recent advances in the research fields connected to inhibition of different types of enzymes, such as Cyclooxygenase-1/Cyclooxygenase-2 (COX-1/COX-2.), Lipoxygenase (LOX), Protein tyrosine phosphatase 1B (PTP-1B), Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), reverse transcriptase, integrase, gyrase, MurB, aldose reductase, carbonic anhydrise, etc.

Dr. Athina Geronikaki
Guest Editor

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Keywords

COX/LOX
Reverse transcriptase
Integrase
gyrase
aldose reductase
carbonic anhydrise
PTP-1B

Published Papers (7 papers)

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Research

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29 pages, 5886 KiB

Open AccessFeature PaperArticle

Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid

by Evangelia Tsolaki, Phaedra Eleftheriou, Victor Kartsev, Athina Geronikaki and Anil K. Saxena

Molecules 2018, 23(7), 1621; https://doi.org/10.3390/molecules23071621 - 03 Jul 2018

Cited by 35 | Viewed by 4136

Abstract

5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15–20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 μΜ and 165 μΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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26 pages, 9928 KiB

Open AccessArticle

Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme from Pseudomonas fluorescens and In Silico Molecular Modeling

by Erika Tovar-Gudiño, Juan Alberto Guevara-Salazar, José Raúl Bahena-Herrera, José Guadalupe Trujillo-Ferrara, Zuleyma Martínez-Campos, Rodrigo Said Razo-Hernández, Ángel Santiago, Nina Pastor and Mario Fernández-Zertuche

Molecules 2018, 23(5), 1128; https://doi.org/10.3390/molecules23051128 - 09 May 2018

Cited by 9 | Viewed by 6032

Abstract

γ-Aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system, and a deficiency of GABA is associated with serious neurological disorders. Due to its low lipophilicity, there has been an intensive search for new molecules with increased lipophilicity to cross the blood-brain barrier to raise GABA concentrations. We have designed and evaluated in vitro and in silico some new analogues of GABA, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These modifications lead to compounds with inhibitory activity as it occurs with compounds 18a and 19a. The construction of Pseudomonas fluorescens and human GABA-AT models were carried out by homology modeling. Docking assays were done for these compounds over the GABA-AT enzyme models where 19a showed a strong interaction with both GABA-AT enzymes. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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16 pages, 11391 KiB

Open AccessArticle

Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors

by Althaf Shaik, Rashmi Bhakuni and Sivapriya Kirubakaran

Molecules 2018, 23(5), 992; https://doi.org/10.3390/molecules23050992 - 24 Apr 2018

Cited by 11 | Viewed by 5833

Abstract

Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC₅₀ = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC₅₀ = 28 nmol/L) and ATR (EC₅₀ = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo^® assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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18 pages, 1324 KiB

Open AccessArticle

4-Thiazolidinone Derivatives as MMP Inhibitors in Tissue Damage: Synthesis, Biological Evaluation and Docking Studies

by Matteo Incerti, Lucia Crascì, Paola Vicini, Esin Aki, Ismail Yalcin, Tugba Ertan-Bolelli, Venera Cardile, Adriana Carol Eleonora Graziano and Annamaria Panico

Molecules 2018, 23(2), 415; https://doi.org/10.3390/molecules23020415 - 14 Feb 2018

Cited by 10 | Viewed by 4610

Abstract

Nine 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)propanamides combining a benzisothiazole and 4-thiazolidinone in one framework were designed and synthesized. The aim of the study was to verify their effectiveness to affect the inflammatory/oxidative process in which free oxygen and nitrite (ROS and RNS) radicals, inflammatory mediators, such as nuclear factor κB (NF-κB), and matrix metalloproteinases (MMPs) are involved. Docking studies of all the compounds were performed in order to explore their binding mode at the MMP-9 protein. An appreciable anti-inflammatory/potential wound healing effects of the tested compounds was highlighted. Derivative 23, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the highest activity, being able to inhibit MMP-9 at nanomolar level(IC₅₀ = 40 nM). Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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16 pages, 889 KiB

Open AccessReview

Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review

by Olga Tarasova, Vladimir Poroikov and Alexander Veselovsky

Molecules 2018, 23(5), 1233; https://doi.org/10.3390/molecules23051233 - 21 May 2018

Cited by 38 | Viewed by 7016

Abstract

Currently, millions of people are living with human immunodeficiency virus type 1 (HIV-1), which causes acquired immunodeficiency syndrome. However, the spread of the HIV-1 resistance to antiviral agents is the major problem in the antiretroviral therapy and medical management of HIV-infected patients. HIV-1 reverse transcriptase (RT) is one of the key viral targets for HIV-1 inhibition. Therefore, the studies on the combatting the HIV resistance that occurs due to the structural changes in RT, are in great demand. This work aims to provide an overview of the state-of-the-art molecular docking approaches applied to the studies of the HIV-1 resistance, associated with RT structure changes. We have reviewed recent studies using molecular docking with mutant forms of RT. The work discusses the modifications of molecular docking, which have been developed to find the novel molecules active against resistance mutants of RT and/or recombinant strains of HIV-1. The perspectives of the existing algorithms of molecular docking to the studies on molecular mechanisms of resistance and selection of the correct binding poses for the reverse transcriptase inhibitors are discussed. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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20 pages, 2124 KiB

Open AccessReview

HIV Resistance Prediction to Reverse Transcriptase Inhibitors: Focus on Open Data

by Olga Tarasova and Vladimir Poroikov

Molecules 2018, 23(4), 956; https://doi.org/10.3390/molecules23040956 - 19 Apr 2018

Cited by 16 | Viewed by 4463

Abstract

Research and development of new antiretroviral agents are in great demand due to issues with safety and efficacy of the antiretroviral drugs. HIV reverse transcriptase (RT) is an important target for HIV treatment. RT inhibitors targeting early stages of the virus-host interaction are of great interest for researchers. There are a lot of clinical and biochemical data on relationships between the occurring of the single point mutations and their combinations in the pol gene of HIV and resistance of the particular variants of HIV to nucleoside and non-nucleoside reverse transcriptase inhibitors. The experimental data stored in the databases of HIV sequences can be used for development of methods that are able to predict HIV resistance based on amino acid or nucleotide sequences. The data on HIV sequences resistance can be further used for (1) development of new antiretroviral agents with high potential for HIV inhibition and elimination and (2) optimization of antiretroviral therapy. In our communication, we focus on the data on the RT sequences and HIV resistance, which are available on the Internet. The experimental methods, which are applied to produce the data on HIV-1 resistance, the known data on their concordance, are also discussed. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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21 pages, 4810 KiB

Open AccessReview

Thiazoles and Thiazolidinones as COX/LOX Inhibitors

by Konstantinos Liaras, Maria Fesatidou and Athina Geronikaki

Molecules 2018, 23(3), 685; https://doi.org/10.3390/molecules23030685 - 18 Mar 2018

Cited by 111 | Viewed by 9350

Abstract

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Τhiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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