Molecules

Editorial

Jump to: Research, Review

5 pages, 193 KiB

Open AccessEditorial

Recent Trends in Enzyme Inhibition and Activation in Drug Design

by Athina Geronikaki

Molecules 2021, 26(1), 17; https://doi.org/10.3390/molecules26010017 - 22 Dec 2020

Cited by 15 | Viewed by 3305

Abstract

It is known that enzymes are involved in many pathological conditions, such as inflammation, diabetes, microbial infections, HIV, neoplastic, neglected diseases and others [...] Full article

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

Research

Jump to: Editorial, Review

15 pages, 5718 KiB

Open AccessFeature PaperArticle

Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies

by Vladimir P. Berishvili, Alexander N. Kuimov, Andrew E. Voronkov, Eugene V. Radchenko, Pradeep Kumar, Yahya E. Choonara, Viness Pillay, Ahmed Kamal and Vladimir A. Palyulin

Molecules 2020, 25(14), 3171; https://doi.org/10.3390/molecules25143171 - 11 Jul 2020

Cited by 18 | Viewed by 4654

Abstract

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, [...] Read more.

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC₅₀ values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages. Full article

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

► Show Figures

Figure 1

15 pages, 1826 KiB

Open AccessCommunication

Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

by Olga Tarasova, Sergey Ivanov, Dmitry A. Filimonov and Vladimir Poroikov

Molecules 2020, 25(12), 2944; https://doi.org/10.3390/molecules25122944 - 26 Jun 2020

Cited by 11 | Viewed by 4089

Abstract

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is [...] Read more.

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation. Full article

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

► Show Figures

Figure 1

17 pages, 5976 KiB

Open AccessArticle

Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities

by Piotr Maj, Mattia Mori, Justyna Sobich, Joanna Markowicz, Łukasz Uram, Zbigniew Zieliński, Deborah Quaglio, Andrea Calcaterra, Ylenia Cau, Bruno Botta and Wojciech Rode

Molecules 2020, 25(12), 2894; https://doi.org/10.3390/molecules25122894 - 23 Jun 2020

Cited by 2 | Viewed by 3157

Abstract

With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. [...] Read more.

With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells. Full article

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

► Show Figures

Graphical abstract

22 pages, 9726 KiB

Open AccessArticle

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

by Yanlin Jian, Fabian Hulpia, Martijn D. P. Risseeuw, He Eun Forbes, Guy Caljon, Hélène Munier-Lehmann, Helena I. M. Boshoff and Serge Van Calenbergh

Molecules 2020, 25(12), 2805; https://doi.org/10.3390/molecules25122805 - 17 Jun 2020

Cited by 5 | Viewed by 2736

Abstract

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold [...] Read more.

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC₅₀-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM). Full article

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

► Show Figures

Graphical abstract

20 pages, 7066 KiB

Open AccessArticle

In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus

by Phaedra Eleftheriou, Dionysia Amanatidou, Anthi Petrou and Athina Geronikaki

Molecules 2020, 25(11), 2529; https://doi.org/10.3390/molecules25112529 - 29 May 2020

Cited by 57 | Viewed by 7395

Abstract

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has [...] Read more.

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia. Full article

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

► Show Figures

Graphical abstract

16 pages, 3442 KiB

Open AccessFeature PaperArticle

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

by Nadezhda Novichikhina, Ivan Ilin, Anna Tashchilova, Alexey Sulimov, Danil Kutov, Irina Ledenyova, Mikhail Krysin, Khidmet Shikhaliev, Anna Gantseva, Ekaterina Gantseva, Nadezhda Podoplelova and Vladimir Sulimov

Molecules 2020, 25(8), 1889; https://doi.org/10.3390/molecules25081889 - 19 Apr 2020

Cited by 25 | Viewed by 4161

Abstract

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of [...] Read more.

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C^6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC₅₀ value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor. Full article

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

► Show Figures

Graphical abstract

19 pages, 1280 KiB

Open AccessArticle

2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication

by Angela Corona, Valentina Onnis, Claudia Del Vecchio, Francesca Esposito, Yung-Chi Cheng and Enzo Tramontano

Molecules 2020, 25(6), 1338; https://doi.org/10.3390/molecules25061338 - 15 Mar 2020

Cited by 13 | Viewed by 4397

Abstract

The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of [...] Read more.

The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC₅₀ of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects. Full article

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

► Show Figures

Figure 1

25 pages, 15058 KiB

Open AccessArticle

1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

by Jenny Desantis, Serena Massari, Angela Corona, Andrea Astolfi, Stefano Sabatini, Giuseppe Manfroni, Deborah Palazzotti, Violetta Cecchetti, Christophe Pannecouque, Enzo Tramontano and Oriana Tabarrini

Molecules 2020, 25(5), 1183; https://doi.org/10.3390/molecules25051183 - 5 Mar 2020

Cited by 25 | Viewed by 5096

Abstract

Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of [...] Read more.

Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (III_B strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors. Full article

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

► Show Figures

Graphical abstract

12 pages, 2928 KiB

Open AccessArticle

(Q)SAR Models of HIV-1 Protein Inhibition by Drug-Like Compounds

by Leonid A. Stolbov, Dmitry S. Druzhilovskiy, Dmitry A. Filimonov, Marc C. Nicklaus and Vladimir V. Poroikov

Molecules 2020, 25(1), 87; https://doi.org/10.3390/molecules25010087 - 25 Dec 2019

Cited by 5 | Viewed by 3300

Abstract

Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict [...] Read more.

Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict the interaction of drug-like compounds with multiple targets for HIV treatment, ligand-based drug design approach is widely applied. In this study, we evaluated the possibilities and limitations of (Q)SAR analysis aimed at the discovery of novel antiretroviral agents inhibiting the vital HIV enzymes. Local (Q)SAR models are based on the analysis of structure–activity relationships for molecules from the same chemical class, which significantly restrict their applicability domain. In contrast, global (Q)SAR models exploit data from heterogeneous sets of drug-like compounds, which allows their application to databases containing diverse structures. We compared the information for HIV-1 integrase, protease and reverse transcriptase inhibitors available in the EBI ChEMBL, NIAID HIV/OI/TB Therapeutics, and Clarivate Analytics Integrity databases as the sources for (Q)SAR training sets. Using the PASS and GUSAR software, we developed and validated a variety of (Q)SAR models, which can be further used for virtual screening of new antiretrovirals in the SAVI library. The developed models are implemented in the freely available web resource AntiHIV-Pred. Full article

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

► Show Figures

Graphical abstract

16 pages, 2865 KiB

Open AccessArticle

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones

by Mariagrazia Rullo, Marco Catto, Antonio Carrieri, Modesto de Candia, Cosimo Damiano Altomare and Leonardo Pisani

Molecules 2019, 24(24), 4507; https://doi.org/10.3390/molecules24244507 - 9 Dec 2019

Cited by 16 | Viewed by 3367

Abstract

A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor ( [...] Read more.

A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC₅₀ against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes. Full article

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

► Show Figures

Graphical abstract

18 pages, 6824 KiB

Open AccessFeature PaperArticle

Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X

by Annalaura Brai, Stefania Ronzini, Valentina Riva, Lorenzo Botta, Claudio Zamperini, Matteo Borgini, Claudia Immacolata Trivisani, Anna Garbelli, Carla Pennisi, Adele Boccuto, Francesco Saladini, Maurizio Zazzi, Giovanni Maga and Maurizio Botta

Molecules 2019, 24(21), 3988; https://doi.org/10.3390/molecules24213988 - 4 Nov 2019

Cited by 36 | Viewed by 4665

Abstract

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase [...] Read more.

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development. Full article

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

► Show Figures

Graphical abstract

7 pages, 837 KiB

Open AccessArticle

Prediction of Severity of Drug-Drug Interactions Caused by Enzyme Inhibition and Activation

by Alexander Dmitriev, Dmitry Filimonov, Alexey Lagunin, Dmitry Karasev, Pavel Pogodin, Anastasiya Rudik and Vladimir Poroikov

Molecules 2019, 24(21), 3955; https://doi.org/10.3390/molecules24213955 - 31 Oct 2019

Cited by 14 | Viewed by 3434

Abstract

Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition [...] Read more.

Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition of the victim drug. Accurate assessment of clinically relevant DDIs for novel drug candidates represents one of the significant tasks of contemporary drug research and development and is important for practicing physicians. This work is a development of our previous investigations and aimed to create a model for the severity of DDIs prediction. PASS program and PoSMNA descriptors were implemented for prediction of all five classes of DDIs severity according to OpeRational ClassificAtion (ORCA) system: contraindicated (class 1), provisionally contraindicated (class 2), conditional (class 3), minimal risk (class 4), no interaction (class 5). Prediction can be carried out both for known drugs and for new, not yet synthesized substances using only their structural formulas. Created model provides an assessment of DDIs severity by prediction of different ORCA classes from the first most dangerous class to the fifth class when DDIs do not take place in the human organism. The average accuracy of DDIs class prediction is about 0.75. Full article

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

► Show Figures

Figure 1

18 pages, 5038 KiB

Open AccessArticle

Novel Hit Compounds as Putative Antifungals: The Case of Aspergillus fumigatus

by Eftichia Kritsi, Minos-Timotheos Matsoukas, Constantinos Potamitis, Anastasia Detsi, Marija Ivanov, Marina Sokovic and Panagiotis Zoumpoulakis

Molecules 2019, 24(21), 3853; https://doi.org/10.3390/molecules24213853 - 25 Oct 2019

Cited by 21 | Viewed by 3476

Abstract

The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely [...] Read more.

The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely used category for the treatment of fungal infections. However, increasingly, azole-resistant strains constitute a major problem to be faced. Towards this direction, our study focused on the identification of compounds bearing novel structural motifs which may evolve as a new class of antifungals. To fulfil this scope, a combination of in silico techniques and in vitro assays were implemented. Specifically, a ligand-based pharmacophore model was created and served as a 3D search query to screen the ZINC chemical database. Additionally, molecular docking and molecular dynamics simulations were used to improve the reliability and accuracy of virtual screening results. In total, eight compounds, bearing completely different chemical scaffolds from the commercially available azoles, were proposed and their antifungal activity was evaluated using in vitro assays. Results indicated that all tested compounds exhibit antifungal activity, especially compounds 1, 2, and 4, which presented the most promising minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values and, therefore, could be subjected to further hit to lead optimization. Full article

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

► Show Figures

Graphical abstract

29 pages, 4991 KiB

Open AccessArticle

Novel Thiazolidin-4-ones as Potential Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

by Anthi Petrou, Phaedra Eleftheriou, Athina Geronikaki, Melpomeni G. Akrivou and Ioannis Vizirianakis

Molecules 2019, 24(21), 3821; https://doi.org/10.3390/molecules24213821 - 23 Oct 2019

Cited by 28 | Viewed by 3953

Abstract

Background: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research [...] Read more.

Background: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. Methods: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. Results: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC₅₀ values than nevirapine (0.3 μΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. Conclusion: Twenty four of the tested compounds exhibited inhibitory action lower than 4 μΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC₅₀ values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM. Full article

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

► Show Figures

Graphical abstract

29 pages, 13077 KiB

Open AccessArticle

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

by Katalin Szilágyi, István Hajdú, Beáta Flachner, Zsolt Lőrincz, Júlia Balczer, Péter Gál, Péter Závodszky, Chiara Pirli, Balázs Balogh, István M. Mándity, Sándor Cseh and György Dormán

Molecules 2019, 24(20), 3641; https://doi.org/10.3390/molecules24203641 - 9 Oct 2019

Cited by 12 | Viewed by 4382

Abstract

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since [...] Read more.

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively. Full article

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

► Show Figures

Figure 1

12 pages, 2296 KiB

Open AccessArticle

Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

by Victor Kartsev, Athina Geronikaki, Silvia Bua, Alessio Nocentini, Anthi Petrou, Boris Lichitsky, Mykhaylo Frasinyuk, Janis Leitans, Andris Kazaks, Kaspars Tars and Claudiu T. Supuran

Molecules 2019, 24(19), 3580; https://doi.org/10.3390/molecules24193580 - 4 Oct 2019

Cited by 8 | Viewed by 3053

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO₂ hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, [...] Read more.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO₂ hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets. Full article

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

► Show Figures

Figure 1

12 pages, 2159 KiB

Open AccessFeature PaperArticle

Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam

by Panagiotis Theodosis-Nobelos, Georgios Papagiouvannis, Panos N. Kourounakis and Eleni A. Rekka

Molecules 2019, 24(18), 3277; https://doi.org/10.3390/molecules24183277 - 9 Sep 2019

Cited by 17 | Viewed by 3797

Abstract

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic [...] Read more.

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress. Full article

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

► Show Figures

Graphical abstract

19 pages, 8407 KiB

Open AccessArticle

Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-N-Oxide Derivatives

by Florencia Ferraro, Alicia Merlino, Jorge Gil, Hugo Cerecetto, Ileana Corvo and Mauricio Cabrera

Molecules 2019, 24(13), 2348; https://doi.org/10.3390/molecules24132348 - 26 Jun 2019

Cited by 9 | Viewed by 3387

Abstract

Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug [...] Read more.

Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC₅₀ of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases. Full article

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

► Show Figures

Figure 1

16 pages, 4556 KiB

Open AccessArticle

In Vitro and In Silico Evaluation of Bikaverin as a Potent Inhibitor of Human Protein Kinase CK2

by Samer Haidar, Dagmar Aichele, Robin Birus, Janine Hielscher, Tuomo Laitinen, Antti Poso and Joachim Jose

Molecules 2019, 24(7), 1380; https://doi.org/10.3390/molecules24071380 - 8 Apr 2019

Cited by 20 | Viewed by 3831

Abstract

Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural [...] Read more.

Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural compound bikaverin can fit well in the ATP binding site of the target enzyme CK2. By further in vitro evaluation using CK2 holoenzyme, bikaverin turned to be a potent inhibitor with an IC₅₀ value of 1.24 µM. In this work, the cell permeability of bikaverin was determined using a Caco-2 cell permeability assay as a prerequisite for cellular evaluation and the compound turned out to be cell permeable with a P_app- value of 4.46 × 10⁻⁶ cm/s. Bikaverin was tested for its effect on cell viability using a MTT assay and cell proliferation using an EdU assay in different cancer cell lines (MCF7, A427 and A431 cells). Cell viability and cell proliferation were reduced dramatically after treatment with 10 µM bikaverin for 24 h. Additionally the IncuCyte^® live-cell imaging system was applied for monitoring the cytotoxicity of bikaverin in the three tested cancer cell lines. Finally, molecular dynamic studies were performed to clarify the ligand binding mode of bikaverin at the ATP binding site of CK2 and to identify the amino acids involved. Full article

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

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

28 pages, 5609 KiB

Open AccessFeature PaperReview

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

by Adriana Coricello, Francesco Mesiti, Antonio Lupia, Annalisa Maruca and Stefano Alcaro

Molecules 2020, 25(15), 3321; https://doi.org/10.3390/molecules25153321 - 22 Jul 2020

Cited by 29 | Viewed by 6885

Abstract

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application [...] Read more.

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up. Full article

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

► Show Figures

Figure 1

15 pages, 1652 KiB

Open AccessReview

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

by Giuseppe Cianciolo, Antonio De Pascalis, Lorenzo Gasperoni, Francesco Tondolo, Fulvia Zappulo, Irene Capelli, Maria Cappuccilli and Gaetano La Manna

Molecules 2020, 25(12), 2757; https://doi.org/10.3390/molecules25122757 - 15 Jun 2020

Cited by 23 | Viewed by 7150

Abstract

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site [...] Read more.

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis. Full article

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

► Show Figures

Figure 1

Journal Menu

Journal Browser

Recent Trends on Enzymes Inhibitors and Activators in Drug Research II

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (22 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI