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Special Issue "Design and Synthesis of Protease Inhibitors"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 December 2019).

Special Issue Editor

Prof. Dr. Florenci V. González
Website
Guest Editor
Departament de química inorgànica i orgànica, Universitat Jaume I, Spain
Interests: medicinal chemistry; organic synthesis; drug discovery; chemical probes; protease inhibitors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Proteases are enzyme-hydrolyzing peptide bonds of proteins and peptides. They are ubiquitious in nature and are associated with vital biological pathways. Hence, the inhibition of proteases has become a valuable strategy for the search for new drugs against a number of diverse diseases. For example, some aspartyl protease inhibitors are drugs used to control the HIV virus and treat AIDS, serine protease inhibitors are used for the treatment of hepatitis C and some proteasome inhibitors are commercial drugs used to treat multiple myeloma. Some inhibitors of cysteine proteases belonging to the papain superfamily are promising drugs against tropical infectious diseases as Chagas disease, sleeping sickness, Leishmaniasis, malaria and amebiasis. The inhibition of human cathepsins is also a strategy for new therapies against Alzheimer’s disease, cancer (cathepsin B) and osteoporosis (cathepsin K).

Although some proteases were recognized as targets a few decades ago, a vast number of inhibitors have been reported. Many of the reported protease inhibitors are synthetic compounds that have been designed from the crystallographic structure of the protease, but some of them are natural products. A search for the key terms “protease” and “inhibitor” in the ISI-Web of Knowledge database in October, 2018, produced 126,198 hits in ten areas (biochemistry and molecular biology, pharmacology pharmacy, immunology, genetics heredity, cell biology, infectious diseases, chemistry, microbiology, hematology and cardiovascular system cardiology) indicating the importance of protease inhibitors.

Reported proteases inhibitors can be classified into a few types according to their inhibition kinetics. Some inhibitors display a reactive moiety in their chemical structure acting as an electrophilic trap to react covalently with corresponding nucleophilic residue in the active center, mostly acting as irreversible inhibitors, but some of them act as reversible inhibitors (covalent reversible inhibitors). Interestingly, irreversible protease inhibitors have found interesting applications in the search of new targets and visualization in cell studies by their derivatization into chemical probes. Conversely, non-covalent reversible inhibitors do not form any covalent bond with the target, displaying key moieties in the chemical structure to furnish high binding affinity for the target.

Computational studies such as docking or especially QM/MM calculations represent very important tools for the design of new inhibitors and for rationalizing the mode-of-action of inhibitors against the targets.

This forthcoming Special Issue of Molecules entitled “Design and Synthesis of Proteases Inhibitors“ will focus on recent advances in protease inhibitors, covering the synthesis of protease inhibitors, the design of new chemical entities acting as inhibitors of proteases, and the new applications to which these interesting compounds are contributing.

Prof. Florenci V. González
Guest Editor

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 papers will be 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. Molecules is an international peer-reviewed open access semimonthly 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 2000 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

  • Protease inhibitor
  • Organic synthesis
  • Medicinal chemistry
  • Computational studies (docking, QM/MM)
  • Chemical probes

Published Papers (2 papers)

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Research

Open AccessArticle
Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation
Molecules 2019, 24(24), 4479; https://doi.org/10.3390/molecules24244479 - 06 Dec 2019
Abstract
Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so [...] Read more.
Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure–activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q 2 = 0.623, r 2 = 0.987, r pred 2 = 0.857) and comparative molecular similarity indices analysis (CoMSIA q 2 = 0.728, r 2 = 0.960, r pred 2 = 0.899) were used to establish the model, and the structure–activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future. Full article
(This article belongs to the Special Issue Design and Synthesis of Protease Inhibitors)
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Open AccessArticle
New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin
Molecules 2019, 24(21), 3887; https://doi.org/10.3390/molecules24213887 - 28 Oct 2019
Cited by 2
Abstract
Protease inhibition has led to treating many diseases and has been successful in producing many commercial drugs by pharmaceutical companies. Among many proteases, serine protease has been attractive in treating metabolic disorder diabetes mellitus (DM). Gliptins have been proven to inhibit dipeptidyl peptidase-4 [...] Read more.
Protease inhibition has led to treating many diseases and has been successful in producing many commercial drugs by pharmaceutical companies. Among many proteases, serine protease has been attractive in treating metabolic disorder diabetes mellitus (DM). Gliptins have been proven to inhibit dipeptidyl peptidase-4 (DPP4), a serine protease, and are an emerging therapeutic drug target to reduce blood glucose levels, but until now there is no natural cyclic peptide proven to inhibit serine protease DPP4. This study demonstrates the potential mechanism of natural cyclic peptide oxytocin (OXT) as a DPP4 inhibitor. To achieve this, initially, activity atlas and field-based models of DPP4 inhibitors were utilized to predict the possible features of positive and negative electrostatic, hydrophobic, and activity shapes of DPP4 inhibition. Oxytocin binding mode, flexibility, and interacting residues were studied using molecular docking simulations studies. 3D-RISM calculations studies revealed that the stability of water molecules at the binding site are favorable. Finally, an experimental study using fluorescence assay revealed OXT inhibits DPP4 in a concentration-dependent manner in a significant way (p < 0.05) and possess IC50 of 110.7 nM. These new findings significantly expand the pharmaceutical application of cyclic peptides, and in specific OXT, and implicate further optimization of OXT inhibition capacity to understand the effect of DPP4 inhibition. This work highlights the development of natural cyclic peptides as future therapeutic peptides to reduce glucose levels and treat diabetes mellitus. Full article
(This article belongs to the Special Issue Design and Synthesis of Protease Inhibitors)
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