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Special Issue "Fragment Based Drug Discovery"

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

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editor

Prof. Dr. Brian J. Stockman
Website
Guest Editor
Department of Chemistry, Adelphi University, Garden City, New York, USA
Interests: fragment-based drug discovery; 1H and 19F NMR-based activity assays; Nucleoside ribohydrolase inhibitors as novel antitrichomonal agents

Special Issue Information

Dear Colleagues,

Fragment-based drug discovery has become widespread in industry and academia. The utility of the approach has been validated by the steadily increasing number of compounds in the clinic that were developed from hits having their origins in fragment screens. The approach continues to be improved by refinements in fragment library design, development of new and often complementary screening methods, and more efficient transitions from fragment hits to structure-guided medicinal chemistry. This Special Issue will disseminate advances in fragment library design and screening methodologies, along with recent applications of fragment-based ligandability assessment and drug discovery to novel pharmaceutical targets.

Prof. Dr. Brian J. Stockman
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

  • Fragment library design
  • Fragment screening
  • Hit-to-lead transition
  • Molecular modeling
  • NMR spectroscopy
  • X-ray crystallography
  • Surface plasmon resonance
  • Target ligandability
  • Protein-protein interaction inhibitors
  • Enzyme inhibitors

Published Papers (7 papers)

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Research

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Open AccessArticle
Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA
Molecules 2020, 25(7), 1760; https://doi.org/10.3390/molecules25071760 - 10 Apr 2020
Abstract
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins [...] Read more.
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Open AccessArticle
Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening
Molecules 2020, 25(1), 237; https://doi.org/10.3390/molecules25010237 - 06 Jan 2020
Cited by 2
Abstract
Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric [...] Read more.
Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Open AccessArticle
Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead
Molecules 2020, 25(1), 147; https://doi.org/10.3390/molecules25010147 - 30 Dec 2019
Abstract
Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental [...] Read more.
Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Open AccessFeature PaperArticle
Multi-Target Chemometric Modelling, Fragment Analysis and Virtual Screening with ERK Inhibitors as Potential Anticancer Agents
Molecules 2019, 24(21), 3909; https://doi.org/10.3390/molecules24213909 - 30 Oct 2019
Cited by 2
Abstract
Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer. The ERK-1/2 inhibitors are thus considered as potential agents for cancer therapy. Multitarget quantitative structure–activity relationship (mt-QSAR) models based [...] Read more.
Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer. The ERK-1/2 inhibitors are thus considered as potential agents for cancer therapy. Multitarget quantitative structure–activity relationship (mt-QSAR) models based on the Box–Jenkins approach were developed with a dataset containing 6400 ERK inhibitors assayed under different experimental conditions. The first mt-QSAR linear model was built with linear discriminant analysis (LDA) and provided information regarding the structural requirements for better activity. This linear model was also utilised for a fragment analysis to estimate the contributions of ring fragments towards ERK inhibition. Then, the random forest (RF) technique was employed to produce highly predictive non-linear mt-QSAR models, which were used for screening the Asinex kinase library and identify the most potential virtual hits. The fragment analysis results justified the selection of the hits retrieved through such virtual screening. The latter were subsequently subjected to molecular docking and molecular dynamics simulations to understand their possible interactions with ERK enzymes. The present work, which utilises in-silico techniques such as multitarget chemometric modelling, fragment analysis, virtual screening, molecular docking and dynamics, may provide important guidelines to facilitate the discovery of novel ERK inhibitors. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Open AccessArticle
The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors
Molecules 2019, 24(20), 3756; https://doi.org/10.3390/molecules24203756 - 18 Oct 2019
Cited by 2
Abstract
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be [...] Read more.
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Open AccessArticle
Development of a Fragment-Based Screening Assay for the Focal Adhesion Targeting Domain Using SPR and NMR
Molecules 2019, 24(18), 3352; https://doi.org/10.3390/molecules24183352 - 14 Sep 2019
Cited by 1
Abstract
The Focal Adhesion Targeting (FAT) domain of Focal Adhesion Kinase (FAK) is a promising drug target since FAK is overexpressed in many malignancies and promotes cancer cell metastasis. The FAT domain serves as a scaffolding protein, and its interaction with the protein paxillin [...] Read more.
The Focal Adhesion Targeting (FAT) domain of Focal Adhesion Kinase (FAK) is a promising drug target since FAK is overexpressed in many malignancies and promotes cancer cell metastasis. The FAT domain serves as a scaffolding protein, and its interaction with the protein paxillin localizes FAK to focal adhesions. Various studies have highlighted the importance of FAT-paxillin binding in tumor growth, cell invasion, and metastasis. Targeting this interaction through high-throughput screening (HTS) provides a challenge due to the large and complex binding interface. In this report, we describe a novel approach to targeting FAT through fragment-based drug discovery (FBDD). We developed two fragment-based screening assays—a primary SPR assay and a secondary heteronuclear single quantum coherence nuclear magnetic resonance (HSQC-NMR) assay. For SPR, we designed an AviTag construct, optimized SPR buffer conditions, and created mutant controls. For NMR, resonance backbone assignments of the human FAT domain were obtained for the HSQC assay. A 189-compound fragment library from Enamine was screened through our primary SPR assay to demonstrate the feasibility of a FAT-FBDD pipeline, with 19 initial hit compounds. A final total of 11 validated hits were identified after secondary screening on NMR. This screening pipeline is the first FBDD screen of the FAT domain reported and represents a valid method for further drug discovery efforts on this difficult target. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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Review

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Open AccessReview
Concepts and Core Principles of Fragment-Based Drug Design
Molecules 2019, 24(23), 4309; https://doi.org/10.3390/molecules24234309 - 26 Nov 2019
Cited by 2
Abstract
In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library selection/construction over biophysical screening and evaluation methods to in-depth hit qualification and subsequent optimization strategies are discussed. These principles can [...] Read more.
In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library selection/construction over biophysical screening and evaluation methods to in-depth hit qualification and subsequent optimization strategies are discussed. These principles can be generally applied to most classes of drug targets. The examples given for fragment growing, merging, and linking strategies at the end of the review are set in the fields of enzyme-inhibitor design and macromolecule–macromolecule interaction inhibition. Building upon the foundation of fragment-based drug discovery (FBDD) and its methodologies, we also highlight a few new trends in FBDD. Full article
(This article belongs to the Special Issue Fragment Based Drug Discovery)
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