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Molecules
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Small Molecule Inhibitors and Probes of Therapeutically-Relevant Enzymes
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Small Molecule Inhibitors and Probes of Therapeutically-Relevant Enzymes

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 8767

Special Issue Editors

Dr. Sanjai Kumar Pathak

E-Mail Website
Guest Editor
Chemistry and Biochemistry Department, Queens College of The City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, USA
Interests: chemical biology of protein phosphorylation and proteolytic enzymes; inhibitor and probe development for functional proteomics; computational drug design
Dr. Dibyendu Dana

E-Mail Website
Guest Editor
Chemistry and Biochemistry Department, Queens College of The City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, USA
Interests: preclinical drug development; design and development of inhibitors and probes; enzyme assay development

Special Issue Information

Dear Colleagues,

Small molecules such as hormones, natural products, metabolites, and neurotransmitters make critical connections in functional networks of both normal and disease cells. They do so by mediating specific interactions with their biological targets, thereby initiating, amplifying, or antagonizing a cellular signal. Unfortunately, in human diseases, these very complex yet carefully coordinated cellular signals are often dysregulated, resulting in aberrant signal transduction. Small molecule therapeutics that target specific enzymes to restore normal signal transduction still dominate the list of clinically approved drugs. This success can primarily be attributed to (a) advancement in novel synthetic methodologies for the generation of highly focused libraries that provide significant room for flexibility both during early design and the late stages of development, (b) rapid advancement in structural biology methods, and (c) availability of higher-level computational methods for lead identification and optimization. Furthermore, in recent times, small molecules have also served as robust chemical biology tools for the functional assignment of different enzyme classes. In this Special Issue, unpublished work on the development of small molecule inhibitory compounds of therapeutically relevant enzymes is invited. In addition, exhaustive reviews on the latest development of new types of chemical probes are also welcomed.

Dr. Sanjai Kumar Pathak
Dr. Dibyendu Dana
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. 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 2700 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

  • Small molecule inhibitors
  • Chemical probes
  • Activity-based probes
  • PROTAC
  • Protein kinase inhibitors
  • Enzyme inhibitors
  • Enzyme probes
  • Clickable and tagless activity-based probes
  • Covalent inhibitors

Published Papers (2 papers)

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Review

36 pages, 13288 KiB  
Review
Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development
by Dibyendu Dana, Tuhin Das, Athena Choi, Ashif I. Bhuiyan, Tirtha K. Das, Tanaji T. Talele and Sanjai K. Pathak
Molecules 2022, 27(2), 347; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27020347 - 06 Jan 2022
Cited by 6 | Viewed by 4221
Abstract
Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. [...] Read more.
Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors and Probes of Therapeutically-Relevant Enzymes)
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13 pages, 1460 KiB  
Review
N-Terminomics Strategies for Protease Substrates Profiling
by Mubashir Mintoo, Amritangshu Chakravarty and Ronak Tilvawala
Molecules 2021, 26(15), 4699; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26154699 - 03 Aug 2021
Cited by 12 | Viewed by 3648
Abstract
Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational modification called proteolysis by hydrolyzing peptide bonds in proteins. Given the destructive potential of proteolysis, protease activity is tightly regulated. Dysregulation of protease [...] Read more.
Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational modification called proteolysis by hydrolyzing peptide bonds in proteins. Given the destructive potential of proteolysis, protease activity is tightly regulated. Dysregulation of protease activity has been reported in numerous disease conditions, including cancers, neurodegenerative diseases, inflammatory conditions, cardiovascular diseases, and viral infections. The proteolytic profile of a cell, tissue, or organ is governed by protease activation, activity, and substrate specificity. Thus, identifying protease substrates and proteolytic events under physiological conditions can provide crucial information about how the change in protease regulation can alter the cellular proteolytic landscape. In recent years, mass spectrometry-based techniques called N-terminomics have become instrumental in identifying protease substrates from complex biological mixtures. N-terminomics employs the labeling and enrichment of native and neo-N-termini peptides, generated upon proteolysis followed by mass spectrometry analysis allowing protease substrate profiling directly from biological samples. In this review, we provide a brief overview of N-terminomics techniques, focusing on their strengths, weaknesses, limitations, and providing specific examples where they were successfully employed to identify protease substrates in vivo and under physiological conditions. In addition, we explore the current trends in the protease field and the potential for future developments. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors and Probes of Therapeutically-Relevant Enzymes)
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