Special Issue "Design of Enzyme Inhibitors as Potential Drugs"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 30 June 2019

Special Issue Editor

Guest Editor
Prof. Dr. Pawel Kafarski

Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland
Website | E-Mail
Interests: bioorganic chemistry; medicinal chemistry; drug design; amino acids and peptides; organophosphorus compounds; natural products

Special Issue Information

Dear Colleagues, 

Enzyme inhibitors are used as tools for studying mechanisms of enzymatic catalysis and as compounds for treating certain physiologic disorders. Thus, they remain prime targets for drug design because altering enzyme activity has immediate and defined effects. Their utility as mechanistic therapeutic agents is dependent on both the potency of the inhibitor and its specificity toward its target enzyme. This, in turn, depends on the number and type of interactions the inhibitor makes with the enzyme and the overall mode of inhibition.

Rational drug design requires a multidisciplinary approach with necessity for experimental and theoretical background. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. A feature that characterizes this process for developing potential leads all known theoretical and experimental knowledge of the enzyme under study is used. The rational inhibitor design does not follow a certain single strategy; instead, such a strategy is a consequence of the experience of the   researcher or the collaborative research group.

To achieve a more comprehensive understanding of modes and techniques of design of enzyme inhibitors of medicinal importance, the journal Pharmaceuticals now invites valuable contributions that report original observations, or reviews on that matter.

Prof. Dr. Pawel Kafarski
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. Pharmaceuticals is an international peer-reviewed open access quarterly 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 850 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

  • rational drug design
  • covalent and non-covalent inhibitors
  • structure-based drug design
  • transition-state analogs
  • knowledge-based modeling and design
  • pharmacophore
  • fragment-based approaches in drug discovery
  • structure-based selectivity design
  • multitarget-directed drugs
  • activity-based protein profiling
  • inhibitors of natural origin
  • non-conventional inhibitors.

Published Papers (3 papers)

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Research

Open AccessArticle Assessment of Nonnucleoside Inhibitors Binding to HIV-1 Reverse Transcriptase Using HYDE Scoring
Pharmaceuticals 2019, 12(2), 64; https://doi.org/10.3390/ph12020064 (registering DOI)
Received: 1 April 2019 / Revised: 19 April 2019 / Accepted: 20 April 2019 / Published: 24 April 2019
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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)
Open AccessArticle Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos
Pharmaceuticals 2019, 12(2), 61; https://doi.org/10.3390/ph12020061
Received: 25 February 2019 / Revised: 5 April 2019 / Accepted: 8 April 2019 / Published: 18 April 2019
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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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Open AccessArticle Identification of Potential Inhibitors from Pyriproxyfen with Insecticidal Activity by Virtual Screening
Pharmaceuticals 2019, 12(1), 20; https://doi.org/10.3390/ph12010020
Received: 30 December 2018 / Revised: 17 January 2019 / Accepted: 19 January 2019 / Published: 25 January 2019
Cited by 1 | PDF Full-text (3061 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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