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Special Issue "Trends in the Development of Enzyme Inhibitors"

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

Deadline for manuscript submissions: 31 December 2018

Special Issue Editor

Guest Editor
Prof. Dr. Tiziano Tuccinardi

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Website | E-Mail
Interests: medicinal chemistry; drug design; ligand-protein binding, molecular interactions; molecular modeling; hit identification; lead optimization

Special Issue Information

Dear Colleagues,

This Special Issue is entitled “Trends in the Development of Enzyme Inhibitors”. The identification of small molecules able to inhibit the activity of specific target enzymes is probably one of the most studied and important research fields in the history of drug discovery. Nevertheless, due to the growing amount of information regarding the role of enzymes in various therapeutic areas, this field is still one of the most studied. Thanks to all the reported studies about new enzyme targets that may represent innovative therapeutic opportunities, and also thanks to the development and optimization of novel technologies, the identification of enzyme inhibitors has become a common goal for medicinal chemists and chemical biologists. This Special Issue aims to provide a forum for the dissemination of: a) the latest information on novel approaches for the identification and optimization of enzyme inhibitors and b) research studies reporting the design, synthesis, and biological evaluation of potentially-active inhibitors.

Prof. Dr. Tiziano Tuccinardi
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 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 1800 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

  • medicinal chemistry
  • drug design
  • ligand-protein binding, molecular interactions
  • molecular modeling
  • hit identification
  • lead optimization

Published Papers (2 papers)

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Research

Open AccessArticle Screening of Angiotensin-I Converting Enzyme Inhibitory Peptides Derived from Caulerpa lentillifera
Molecules 2018, 23(11), 3005; https://doi.org/10.3390/molecules23113005 (registering DOI)
Received: 14 October 2018 / Revised: 11 November 2018 / Accepted: 15 November 2018 / Published: 16 November 2018
PDF Full-text (4741 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera
[...] Read more.
Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera (known commonly as sea grape) protein hydrolysate. In this study, short-chain peptides were obtained after hydrolysis by various enzymes and subsequently by ultrafiltration. Thermolysin hydrolysate showed the highest ACEI activity. Bioassay-guided fractionation was performed using reversed-phase high performance liquid chromatography (RP-HPLC) to uncover the fraction 9 with the highest ACE inhibitory activity from thermolysin hydrolysate. Peptides in this fraction were further identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis coupled with de novo sequencing, which gave two oligopeptides, FDGIP (FP-5) and AIDPVRA (AA-7). The identities and activities of these two peptides were further confirmed using synthetic peptides. Their IC50 values were determined as 58.89 ± 0.68 µM and 65.76 ± 0.92 µM, respectively. Moreover, the inhibition kinetics revealed that both FP-5 and AA-7 are competitive inhibitors. These activities were further explained using molecular docking simulation. The present study is the first report about ACEI peptides derived from Caulerpa lentillifera and it shows the potential for preventing hypertension and for functional food development. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Graphical abstract

Open AccessArticle Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors
Molecules 2018, 23(9), 2369; https://doi.org/10.3390/molecules23092369
Received: 12 July 2018 / Revised: 12 September 2018 / Accepted: 13 September 2018 / Published: 17 September 2018
PDF Full-text (3033 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials.
[...] Read more.
Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC50s in the nanomolar range, with 2–130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Graphical abstract

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