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12 pages, 5926 KiB

Open AccessArticle

Phosphonic Acid Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase, Tomato Acidic Leucine Aminopeptidase and Aminopeptidase from Barley Seeds

by Weronika Wanat, Michał Talma, Małgorzata Pawełczak and Paweł Kafarski

Pharmaceuticals 2019, 12(3), 139; https://doi.org/10.3390/ph12030139 - 17 Sep 2019

Cited by 7 | Viewed by 3883

Abstract

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data [...] Read more.

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data served as a basis for studying the binding modes of these inhibitors by pAPN using molecular modeling. It was found that their aminophosphonate fragments were bound in a highly uniform manner and that the difference in their affinities most likely resulted from the mode of substitution of their phenyl rings. The obtained binding modes towards pAPN were compared, with these predicted for bovine lens leucine aminopeptidase (blLAP) and tomato acidic leucine aminopeptidase (tLAPA). The performed studies indicated that the binding manner of the phenylglycine analogs to biLAP and tLAPA are significantly similar and differ slightly from that predicted for pAPN. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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13 pages, 1981 KiB

Open AccessCommunication

α-Glucosidase Inhibitory Activity of Cycloartane-Type Triterpenes Isolated from Indonesian Stingless Bee Propolis and Their Structure–Activity Relationship

by Niken Pujirahayu, Debu Kumar Bhattacharjya, Toshisada Suzuki and Takeshi Katayama

Pharmaceuticals 2019, 12(3), 102; https://doi.org/10.3390/ph12030102 - 01 Jul 2019

Cited by 28 | Viewed by 5995

Abstract

This study reports on the antioxidant activity and α-glucosidase inhibitory activity of five cycloartane-type triterpenes isolated from Indonesian stingless bee (Tetragonula sapiens Cockerell) propolis and their structure–activity relationships. The structure of the triterpenes was determined to include mangiferolic acid (1), [...] Read more.

This study reports on the antioxidant activity and α-glucosidase inhibitory activity of five cycloartane-type triterpenes isolated from Indonesian stingless bee (Tetragonula sapiens Cockerell) propolis and their structure–activity relationships. The structure of the triterpenes was determined to include mangiferolic acid (1), Cycloartenol (2), ambonic acid (3), mangiferonic acid (4), and ambolic acid (5). The inhibitory test results of all isolated triterpenes against α-glucosidase showed a high potential for inhibitory activity with an IC₅₀ range between 2.46 and 10.72 µM. Among the compounds tested, mangiferonic acid (4) was the strongest α-glucosidase inhibitor with IC₅₀ 2.46 µM compared to the standard (–)-epicatechin (1991.1 µM), and also had antioxidant activities with IC₅₀ values of 37.74 ± 6.55 µM. The study on the structure–activity relationships among the compounds showed that the ketone group at C-3 and the double bonds at C-24 and C-25 are needed to increase the α-glucosidase inhibitory activity. The carboxylic group at C-26 is also more important for increasing the inhibitory activity compared with the methyl group. This study provides an approach to help consider the structural requirements of cycloartane-type triterpenes from propolis as α-glucosidase inhibitors. An understanding of these requirements is deemed necessary to find a new type of α-glucosidase inhibitor from the cycloartane-type triterpenes or to improve those inhibitors that are known to help in the treatment of diabetes. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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12 pages, 1853 KiB

Open AccessArticle

Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate

by Isabel C. Henao Castañeda, Jaime A. Pereañez and Lina M. Preciado

Pharmaceuticals 2019, 12(2), 80; https://doi.org/10.3390/ph12020080 - 23 May 2019

Cited by 13 | Viewed by 3883

Abstract

Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible [...] Read more.

Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible for local damage. This work aimed to synthesize thioesters derived from 2-sulfenyl ethylacetate and to evaluate the inhibitory effects on two snake venom toxins. Ethyl 2-((4-chlorobenzoyl)thio)acetate (I), Ethyl 2-((3-nitrobenzoyl)thio)acetate (II) and Ethyl 2-((4-nitrobenzoyl)thio)acetate (III) were synthesized and spectroscopically characterized. Computational calculations were performed to support the study. The inhibitory capacity of compounds (I–III) was evaluated on a phospholipase A₂ (Cdcum6) isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis and the P-I type metalloproteinase Batx-I isolated from Bothrops atrox. I–III inhibited PLA₂ with IC₅₀ values of 193.2, 305.4 and 132.7 µM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC₅₀ of 2774 and 1879 µM. Molecular docking studies show that inhibition of PLA₂ may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca²⁺. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA₂ may occur. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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14 pages, 21137 KiB

Open AccessArticle

Assessment of Nonnucleoside Inhibitors Binding to HIV-1 Reverse Transcriptase Using HYDE Scoring

by Agata Paneth, Wojciech Płonka and Piotr Paneth

Pharmaceuticals 2019, 12(2), 64; https://doi.org/10.3390/ph12020064 - 24 Apr 2019

Cited by 6 | Viewed by 3318

Abstract

In this study, 48 inhibitors were docked to 107 allosteric centers of human immunodeficiency virus 1 (HIV-1) reverse transcriptase from the Protein Data Bank (PDB). Based on the average binding scores, quantitative structure-activity relationship (QSAR) equations were constructed in order to elucidate directions [...] Read more.

In this study, 48 inhibitors were docked to 107 allosteric centers of human immunodeficiency virus 1 (HIV-1) reverse transcriptase from the Protein Data Bank (PDB). Based on the average binding scores, quantitative structure-activity relationship (QSAR) equations were constructed in order to elucidate directions of further development in the design of inhibitors. Such developments, informed by structural data, must have a focus on activity against mutated forms of the enzyme, which are the cause of the emergence of multidrug-resistant viral strains. Docking studies employed the HYDE scoring function. Two types of QSARs have been considered: One based on topological descriptors and the other on structural fragments of the inhibitors. Both methods gave similar results, indicating substructures favoring binding to mutated forms of the enzyme. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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19 pages, 4138 KiB

Open AccessArticle

Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos

by Glauber V. da Costa, Elenilze F. B. Ferreira, Ryan da S. Ramos, Luciane B. da Silva, Ester M. F. de Sá, Alicia K. P. da Silva, Cássio M. Lobato, Raimundo N. P. Souto, Carlos Henrique T. de P. da Silva, Leonardo B. Federico, Joaquín M. C. Rosa and Cleydson B. R. dos Santos

Pharmaceuticals 2019, 12(2), 61; https://doi.org/10.3390/ph12020061 - 18 Apr 2019

Cited by 18 | Viewed by 5781

Abstract

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, [...] Read more.

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, which have shown significant growth. The main control strategy is the elimination of the vector, carried out through various education programs, to change human habits, but the most usual is biological control, together with environmental management and chemical control. The most commonly insecticide used is temephos (an organophosphorus compound), but Aedes aegypti populations have shown resistance and the product is highly toxic, so we chose it as a template molecule to perform a ligand-based virtual screening in the ChemBrigde (DIVERSet-CL subcollection) database, searching for derivatives with similarity in shape (ROCS) and electrostatic potential (EON). Thus, fourty-five molecules were filtered based on their pharmacokinetic and toxicological properties and 11 molecules were selected by a molecular docking study, including binding affinity and mode of interaction. The L46, L66 and L68 molecules show potential inhibitory activity for both the insect (−9.28, −10.08 and −6.78 Kcal/mol, respectively) and human (−6.05, 6.25 and 7.2 Kcal/mol respectively) enzymes, as well as the juvenile hormone protein (−9.2; −10.96 and −8.16 kcal/mol, respectively), showing a significant difference in comparison to the template molecule temephos. Molecules L46, L66 and L68 interacted with important amino acids at each catalytic site of the enzyme reported in the literature. Thus, the molecules here investigated are potential inhibitors for both the acetylcholinesterase enzymes and juvenile hormone protein–from insect and humans, characterizing them as a potential insecticide against the Aedes aegypti mosquito. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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22 pages, 3061 KiB

Open AccessArticle

Identification of Potential Inhibitors from Pyriproxyfen with Insecticidal Activity by Virtual Screening

by Ryan da Silva Ramos, Josivan da Silva Costa, Rai Campos Silva, Glauber Vilhena da Costa, Alex Bruno Lobato Rodrigues, Érica de Menezes Rabelo, Raimundo Nonato Picanço Souto, Carlton Anthony Taft, Carlos Henrique Tomich de Paula da Silva, Joaquín Maria Campos Rosa, Cleydson Breno Rodrigues dos Santos and Williams Jorge da Cruz Macêdo

Pharmaceuticals 2019, 12(1), 20; https://doi.org/10.3390/ph12010020 - 25 Jan 2019

Cited by 39 | Viewed by 6843

Abstract

Aedes aegypti is the main vector of dengue fever transmission, yellow fever, Zika, and chikungunya in tropical and subtropical regions and it is considered to cause health risks to millions of people in the world. In this study, we search to obtain new [...] Read more.

Aedes aegypti is the main vector of dengue fever transmission, yellow fever, Zika, and chikungunya in tropical and subtropical regions and it is considered to cause health risks to millions of people in the world. In this study, we search to obtain new molecules with insecticidal potential against Ae. aegypti via virtual screening. Pyriproxyfen was chosen as a template compound to search molecules in the database Zinc_Natural_Stock (ZNSt) with structural similarity using ROCS (rapid overlay of chemical structures) and EON (electrostatic similarity) software, and in the final search, the top 100 were selected. Subsequently, in silico pharmacokinetic and toxicological properties were determined resulting in a total of 14 molecules, and these were submitted to the PASS online server for the prediction of biological insecticide and acetylcholinesterase activities, and only two selected molecules followed for the molecular docking study to evaluate the binding free energy and interaction mode. After these procedures were performed, toxicity risk assessment such as LD₅₀ values in mg/kg and toxicity class using the PROTOX online server, were undertaken. Molecule ZINC00001624 presented potential for inhibition for the acetylcholinesterase enzyme (insect and human) with a binding affinity value of −10.5 and −10.3 kcal/mol, respectively. The interaction with the juvenile hormone was −11.4 kcal/mol for the molecule ZINC00001021. Molecules ZINC00001021 and ZINC00001624 had excellent predictions in all the steps of the study and may be indicated as the most promising molecules resulting from the virtual screening of new insecticidal agents. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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Review

Jump to: Research

14 pages, 528 KiB

Open AccessReview

Cysteine Cathepsin Protease Inhibition: An update on its Diagnostic, Prognostic and Therapeutic Potential in Cancer

by Surinder M. Soond, Maria V. Kozhevnikova, Paul A. Townsend and Andrey A. Zamyatnin, Jr.

Pharmaceuticals 2019, 12(2), 87; https://doi.org/10.3390/ph12020087 - 11 Jun 2019

Cited by 41 | Viewed by 5956

Abstract

In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic [...] Read more.

In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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16 pages, 3141 KiB

Open AccessReview

Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases

by Marta Maślanka and Artur Mucha

Pharmaceuticals 2019, 12(2), 86; https://doi.org/10.3390/ph12020086 - 10 Jun 2019

Cited by 10 | Viewed by 4078

Abstract

This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous [...] Read more.

This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous features that characterize the phosphonate compounds and their use. First, the synthesis is versatile and allows comprehensive structural modification and diversification. Accordingly, reactivity and specificity of these bioactive molecules can be easily controlled by appropriate adjustments of the side chains and the leaving groups. Secondly, the phosphonates target exclusively serine proteases and leave other oxygen and sulfur nucleophiles intact. Synthetic accessibility, lack of toxicity, and promising pharmacokinetic properties make them good drug candidates. In consequence, the utility of peptidyl diaryl phosphonates continuously increases and involves novel enzymatic targets and innovative aspects of application. For example, conjugation of the structures of specific inhibitors with reporter groups has become a convenient approach to construct activity-based molecular probes capable of monitoring location and distribution of serine proteases. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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