Special Issue "Screening for Biologically Active Compounds"

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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (31 January 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Jonathan B. Baell

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville VIC 3052, Australia
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Special Issue Information

Dear Colleagues,

High throughput screening (HTS) has come a long way since the first time in the late 1980s that it was implemented in a truly automated fashion. It has become a mainstay as a starting point for the discovery of new drugs, with a particular utility in discovering new chemistry for new biology. Recent technological advances in assay methodologies have been outstanding, in part facilitating access to HTS by increasingly large numbers of academic researchers. This has imparted to HTS an extra level of exploratory research, with a particular focus on chemical biology and tool compound discovery and development. In addition to target-based screening, phenotypic screening is gaining an increasing and in some areas dominating foothold. However, HTS is not an instant solution to drug discovery, because there is no such thing. Assay artefacts continue to be the bane of the hit discovery researcher. Some targets are shown to be undruggable. This special issue will focus on all these aspects of state-of-the-art high throughput screening.

Prof. Dr. Jonathan B. Baell
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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.

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Keywords

  • HTS
  • phenotypic screening
  • target-based screening
  • hit discovery
  • hit-to-Lead optimization
  • hit triage
  • assay artefacts

Published Papers (7 papers)

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Research

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Open AccessArticle A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain
Biology 2014, 3(4), 645-669; doi:10.3390/biology3040645
Received: 23 May 2014 / Revised: 24 September 2014 / Accepted: 24 September 2014 / Published: 17 October 2014
Cited by 6 | PDF Full-text (2067 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351).
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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
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Open AccessArticle In Vitro High Throughput Screening, What Next? Lessons from the Screening for Aurora Kinase Inhibitors
Biology 2014, 3(1), 167-175; doi:10.3390/biology3010167
Received: 3 December 2013 / Revised: 13 February 2014 / Accepted: 14 February 2014 / Published: 27 February 2014
Cited by 1 | PDF Full-text (387 KB) | HTML Full-text | XML Full-text
Abstract
Based on in vitro assays, we performed a High Throughput Screening (HTS) to identify kinase inhibitors among 10,000 small chemical compounds. In this didactic paper, we describe step-by-step the approach to validate the hits as well as the major pitfalls encountered in the
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Based on in vitro assays, we performed a High Throughput Screening (HTS) to identify kinase inhibitors among 10,000 small chemical compounds. In this didactic paper, we describe step-by-step the approach to validate the hits as well as the major pitfalls encountered in the development of active molecules. We propose a decision tree that could be adapted to most in vitro HTS. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
Figures

Open AccessArticle Miniaturized Bioaffinity Assessment Coupled to Mass Spectrometry for Guided Purification of Bioactives from Toad and Cone Snail
Biology 2014, 3(1), 139-156; doi:10.3390/biology3010139
Received: 9 December 2013 / Revised: 23 January 2014 / Accepted: 26 January 2014 / Published: 13 February 2014
Cited by 1 | PDF Full-text (543 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A nano-flow high-resolution screening platform, featuring a parallel chip-based microfluidic bioassay and mass spectrometry coupled to nano-liquid chromatography, was applied to screen animal venoms for nicotinic acetylcholine receptor like (nAChR) affinity by using the acetylcholine binding protein, a mimic of the nAChR. The
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A nano-flow high-resolution screening platform, featuring a parallel chip-based microfluidic bioassay and mass spectrometry coupled to nano-liquid chromatography, was applied to screen animal venoms for nicotinic acetylcholine receptor like (nAChR) affinity by using the acetylcholine binding protein, a mimic of the nAChR. The potential of this microfluidic platform is demonstrated by profiling the Conus textile venom proteome, consisting of over 1,000 peptides. Within one analysis (<90 min, 500 ng venom injected), ligands are detected and identified. To show applicability for non-peptides, small molecular ligands such as steroidal ligands were identified in skin secretions from two toad species (Bufo alvarius and Bufo marinus). Bioactives from the toad samples were subsequently isolated by MS-guided fractionation. The fractions analyzed by NMR and a radioligand binding assay with α7-nAChR confirmed the identity and bioactivity of several new ligands. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
Open AccessArticle High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors
Biology 2014, 3(1), 101-138; doi:10.3390/biology3010101
Received: 7 January 2014 / Revised: 22 January 2014 / Accepted: 22 January 2014 / Published: 10 February 2014
Cited by 4 | PDF Full-text (1360 KB) | HTML Full-text | XML Full-text
Abstract
Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials,
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Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)

Review

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Open AccessReview High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics
Biology 2014, 3(4), 752-780; doi:10.3390/biology3040752
Received: 8 September 2014 / Revised: 28 October 2014 / Accepted: 30 October 2014 / Published: 14 November 2014
Cited by 3 | PDF Full-text (807 KB) | HTML Full-text | XML Full-text
Abstract
Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to
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Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
Open AccessReview Advanced Cell Culture Techniques for Cancer Drug Discovery
Biology 2014, 3(2), 345-367; doi:10.3390/biology3020345
Received: 24 February 2014 / Revised: 16 May 2014 / Accepted: 22 May 2014 / Published: 30 May 2014
Cited by 21 | PDF Full-text (690 KB) | HTML Full-text | XML Full-text
Abstract
Human cancer cell lines are an integral part of drug discovery practices. However, modeling the complexity of cancer utilizing these cell lines on standard plastic substrata, does not accurately represent the tumor microenvironment. Research into developing advanced tumor cell culture models in a
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Human cancer cell lines are an integral part of drug discovery practices. However, modeling the complexity of cancer utilizing these cell lines on standard plastic substrata, does not accurately represent the tumor microenvironment. Research into developing advanced tumor cell culture models in a three-dimensional (3D) architecture that more prescisely characterizes the disease state have been undertaken by a number of laboratories around the world. These 3D cell culture models are particularly beneficial for investigating mechanistic processes and drug resistance in tumor cells. In addition, a range of molecular mechanisms deconstructed by studying cancer cells in 3D models suggest that tumor cells cultured in two-dimensional monolayer conditions do not respond to cancer therapeutics/compounds in a similar manner. Recent studies have demonstrated the potential of utilizing 3D cell culture models in drug discovery programs; however, it is evident that further research is required for the development of more complex models that incorporate the majority of the cellular and physical properties of a tumor. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
Open AccessReview Screening for Antifibrotic Compounds Using High Throughput System Based on Fluorescence Polarization
Biology 2014, 3(2), 281-294; doi:10.3390/biology3020281
Received: 15 January 2014 / Revised: 28 February 2014 / Accepted: 1 April 2014 / Published: 10 April 2014
Cited by 1 | PDF Full-text (931 KB) | HTML Full-text | XML Full-text
Abstract
Fibroproliferative diseases are one of the leading causes of death worldwide. They are characterized by reactive fibrosis caused by uncontrolled synthesis of type I collagen. There is no cure for fibrosis and development of therapeutics that can inhibit collagen synthesis is urgently needed.
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Fibroproliferative diseases are one of the leading causes of death worldwide. They are characterized by reactive fibrosis caused by uncontrolled synthesis of type I collagen. There is no cure for fibrosis and development of therapeutics that can inhibit collagen synthesis is urgently needed. Collagen α1(I) mRNA and α2(I) mRNA encode for type I collagen and they have a unique 5' stem-loop structure in their 5' untranslated regions (5'SL). Collagen 5'SL binds protein LARP6 with high affinity and specificity. The interaction between LARP6 and the 5'SL is critical for biosynthesis of type I collagen and development of fibrosis in vivo. Therefore, this interaction represents is an ideal target to develop antifibrotic drugs. A high throughput system to screen for chemical compounds that can dissociate LARP6 from 5'SL has been developed. It is based on fluorescence polarization and can be adapted to screen for inhibitors of other protein-RNA interactions. Screening of 50,000 chemical compounds yielded a lead compound that can inhibit type I collagen synthesis at nanomolar concentrations. The development, characteristics, and critical appraisal of this assay are presented. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
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