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Pharmaceuticals
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Protease-Based Drug Discovery
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Protease-Based Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (13 May 2023) | Viewed by 5813

Special Issue Editors

Prof. Dr. Ilana Nathan

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Guest Editor
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Interests: molecular mechanisms of necrosis; mitochondria; Lysosomes; reactive oxygen species (ROS); calcium signaling; caspase-independent proteases: serine proteases like CELA, as well as Cathepsin C and B, etc.; protease-based drug development against necrosis: siRNAs, small molecules; relevance to diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Amnon Albeck

E-Mail Website
Guest Editor
Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel
Interests: organic chemistry; peptides and peptidomimetics; biochemistry; enzymology; enzyme mechanisms; enzyme inhibition; proteases; medicinal chemistry; computational biochemistry

Special Issue Information

Dear Colleagues,

This issue will focus on protease inhibitors as potential drugs for a large variety of diseases. Hundreds of proteases are known. They can be divided into four main groups, based on their catalytic machinery (serine-, cysteine-, aspartic- and metalloproteases).

Some proteases function within the living cell, others are membrane-embedded, whereas a third group functions extracellularly. Proteases are involved in many key biological activities, essential for all forms of life. Consequently, they are also involved in many diseases such as high blood pressure, cardiovascular disorders, blood coagulopathies, cancer, viral infections as well as in various modes of cell death: apoptosis, autophagy and necrosis.

Quite a few protease-based drugs are in use, and more are in clinical trials and at different research stages. One of the latest examples is the recently developed Pfizer drug against COVID-19 infection.  Other examples are anti-HIV drugs and protease inhibitors to treat hepatitis C. Of note, some trypsin inhibitors are naturally present in plasma, such as alpha-1 antitrypsin (AAT), used for lung emphysema in AAT-deficient individuals.

This issue provides a glance at this exciting field of proteases as drug targets for the treatment of different diseases. It samples different types of proteases and a variety of diseases associated with protease activity. It sheds light on the difficulties confronting protease-based drug development and strategies to overcome them—and, on a positive note, it convincingly shows the therapeutic potential of development of protease inhibitors for the well-being of humanity. This is further substantiated through the recent evidence that specific proteases are involved in necrotic cell death, and therefore, could establish the basis for the development of new protease inhibitor-based drugs to treat many yet untreatable diseases, as well as for life prolongation (longevity).

Prof. Dr. Ilana Nathan
Prof. Dr. Amnon Albeck
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • proteases inhibitors
  • COVID-19
  • apoptosis
  • necrosis
  • matrix metallo proteinases
  • rhomboid proteases
  • membrane proteases
  • deubiquitinases
  • computational chemistry

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Published Papers (2 papers)

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Research

19 pages, 7801 KiB  
Article
Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro
by Jie Chen, Xiang Zhou, Lifeng Fu and Haiyu Xu
Pharmaceuticals 2023, 16(5), 767; https://doi.org/10.3390/ph16050767 - 19 May 2023
Cited by 6 | Viewed by 2461
Abstract
Drugs that cure COVID-19 have been marketed; however, this disease continues to ravage the world without becoming extinct, and thus, drug discoveries are still relevant. Since Mpro has known advantages as a drug target, such as the conserved nature of the active [...] Read more.
Drugs that cure COVID-19 have been marketed; however, this disease continues to ravage the world without becoming extinct, and thus, drug discoveries are still relevant. Since Mpro has known advantages as a drug target, such as the conserved nature of the active site and the absence of homologous proteins in the body, it receives the attention of many researchers. Meanwhile, the role of traditional Chinese medicine (TCM) in the control of epidemics in China has also led to a focus on natural products, with the hope of finding some promising lead molecules through screening. In this study, we selected a commercial library of 2526 natural products from plants, animals and microorganisms with known biological activity for drug discovery, which had previously been reported for compound screening of the SARS CoV-2 S protein, but had not been tested on Mpro. This library contains compounds from a variety of Chinese herbs, including Lonicerae Japonicae Flos, Forsythiae Fructus and Scutellariae Radix, which are derived from traditional Chinese medicine prescriptions that have been shown to be effective against COVID-19. We used the conventional FRET method for the initial screening. After two rounds of selection, the remaining 86 compounds were divided into flavonoids, lipids, phenylpropanoids, phenols, quinones, alkaloids, terpenoids and steroids according to the skeleton structures, with inhibition rates greater than 70%. The top compounds in each group were selected to test the effective concentration ranges; the IC50 values were as follows: (−)–gallocatechin gallate (1.522 ± 0.126 μM), ginkgolic acid C15:1 (9.352 ± 0.531 μM), hematoxylin (1.025 ± 0.042 μM), fraxetin (2.486 ± 0.178 μM), wedelolactone (1.003 ± 0.238 μM), hydroxytyrosol acetate (3.850 ± 0.576 μM), vanitiolide (2.837 ± 0.225 μM), β,β–dimethylacrylalkannin (2.731 ± 0.308 μM), melanin (7.373 ± 0.368 μM) and cholesteryl sodium sulfate (2.741 ± 0.234μM). In the next step, we employed two biophysical techniques, SPR and nanoDSF, to obtain KD/Kobs values: hematoxylin (0.7 μM), (−)–gallocatechin gallate (126 μM), ginkgolic acid C15:1 (227 μM), wedelolactone (0.9770 μM), β,β–dimethylacrylalkannin (1.9004 μM,), cholesteryl sodium sulfate (7.5950 μM) and melanin (11.5667 μM), which allowed better assessments of the binding levels. Here, seven compounds were the winners. Then, molecular docking experiments were specially performed by AutoDock Vina to analyze the mode of interactions within Mpro and ligands. We finally formulated the present in silico study to predict pharmacokinetic parameters as well as drug-like properties, which is presumably the step that tells humans whether the compounds are drug-like or not. Moreover, hematoxylin, melanin, wedelolactone, β,β–dimethylacrylalkannin and cholesteryl sodium sulfate are in full compliance with the “Lipinski” principle and possess reasonable ADME/T properties, they have a greater potential of being lead compounds. The proposed five compounds are also the first to be found to have potential inhibitory effects on SARS CoV-2 Mpro. We hope that the results in this manuscript may serve as benchmarks for the above potentials. Full article
(This article belongs to the Special Issue Protease-Based Drug Discovery)
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20 pages, 4832 KiB  
Article
Design of Potent Inhibitors Targeting the Main Protease of SARS-CoV-2 Using QSAR Modeling, Molecular Docking, and Molecular Dynamics Simulations
by Mehdi Oubahmane, Ismail Hdoufane, Christelle Delaite, Adlane Sayede, Driss Cherqaoui and Achraf El Allali
Pharmaceuticals 2023, 16(4), 608; https://doi.org/10.3390/ph16040608 - 18 Apr 2023
Cited by 8 | Viewed by 2839
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a serious global public health threat. The evolving strains of SARS-CoV-2 have reduced the effectiveness of vaccines. Therefore, antiviral drugs against SARS-CoV-2 are urgently needed. The main protease (Mpro) of SARS-CoV-2 is an extremely [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a serious global public health threat. The evolving strains of SARS-CoV-2 have reduced the effectiveness of vaccines. Therefore, antiviral drugs against SARS-CoV-2 are urgently needed. The main protease (Mpro) of SARS-CoV-2 is an extremely potent target due to its pivotal role in virus replication and low susceptibility to mutation. In the present study, a quantitative structure–activity relationship (QSAR) study was performed to design new molecules that might have higher inhibitory activity against SARS-CoV-2 Mpro. In this context, a set of 55 dihydrophenanthrene derivatives was used to build two 2D-QSAR models using the Monte Carlo optimization method and the Genetic Algorithm Multi-Linear Regression (GA-MLR) method. From the CORAL QSAR model outputs, the promoters responsible for the increase/decrease in inhibitory activity were extracted and interpreted. The promoters responsible for an increase in activity were added to the lead compound to design new molecules. The GA-MLR QSAR model was used to ensure the inhibitory activity of the designed molecules. For further validation, the designed molecules were subjected to molecular docking analysis and molecular dynamics simulations along with an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. The results of this study suggest that the newly designed molecules have the potential to be developed as effective drugs against SARS-CoV-2. Full article
(This article belongs to the Special Issue Protease-Based Drug Discovery)
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