Special Issue "Screening for Biologically Active Compounds"


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
Website: http://www.monash.edu.au/pharm/research/researchers/profile.html?sid=2520607&pid=7227
E-Mail: Jonathan.Baell@monash.edu

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


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

Published Papers (5 papers)

by ,  and
Biology 2014, 3(2), 345-367; doi:10.3390/biology3020345
Received: 24 February 2014; in revised form: 16 May 2014 / Accepted: 22 May 2014 / Published: 30 May 2014
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by  and
Biology 2014, 3(2), 281-294; doi:10.3390/biology3020281
Received: 15 January 2014; in revised form: 28 February 2014 / Accepted: 1 April 2014 / Published: 10 April 2014
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abstract graphic

by , , ,  and
Biology 2014, 3(1), 167-175; doi:10.3390/biology3010167
Received: 3 December 2013; in revised form: 13 February 2014 / Accepted: 14 February 2014 / Published: 27 February 2014
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abstract graphic

by , , , , , , , , , ,  and
Biology 2014, 3(1), 139-156; doi:10.3390/biology3010139
Received: 9 December 2013; in revised form: 23 January 2014 / Accepted: 26 January 2014 / Published: 13 February 2014
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by , , , , ,  and
Biology 2014, 3(1), 101-138; doi:10.3390/biology3010101
Received: 7 January 2014; in revised form: 22 January 2014 / Accepted: 22 January 2014 / Published: 10 February 2014
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: In Vitro HTS, What Next? Lesson from the Screening for Aurora Kinase Inhibitors.
Authors: Thi-My-Nhung Hoang, Hong-Lien Vu, Ly-Thuy-Tram Le and Annie Molla *
Affiliation: INSERM UJF U823 Institut Albert Bonniot BP 170, 38 042 Grenoble cedex 9, France; E-Mail: annie.molla@ujf-grenoble.fr
Abstract: Based on in vitro assays, we performed a HTS screen, for kinase inhibitors, among 10 000 small compounds. In this didactic review, we described step by step the approach to validate the hits as well as major pitfalls encountered in the development of active molecules. We proposed a decision tree that could be adapted to most in vitro HTS.

Type of Paper: Review
Title: Screening for Antifibrotic Compounds Using High Throughput System Based on Fluorescence Polarization
Authors: Lela Stefanovic and Branko Stefanovic
Affiliation: Dept. of Biomedical Sciences, College of Medicine, Florida State University, 1115 W. Call st., Tallahassee, FL, 32306, USA; E-Mail: branko.stefanovic@med.fsu.edu
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. The ideal antifibrotic drugs must target the regulatory steps which are specific for collagen biosynthesis. Collagen α1(I) mRNA and α2(I) mRNA encode for type I collagen and 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. Knock in mice with mutation of 5’SL in the collagen α1(I) gene develop only minimal fibrosis compared to wt littermates. Likewise, knock down of LARP6 in collagen producing cells dramatically decreases type I collagen synthesis. Thus, the interaction between LARP6 and the 5’SL is critical for biosynthesis of type I collagen and 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 utility of this high throughput system will be described.

Type of Paper: Article
Title: High-Throughput Screening Heading for New Compounds Enhancing Carbapenem Activity against Gram-Negative Bacteria
Authors: Olga Genilloud, et al.
Affiliation: Fundación MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain; E-Mail: olga.genilloud@medinaandalucia.es
Abstract: Novel antibacterial agents for treating Gram-negative bacteria infections are currently one of the most important unmet medical needs. The growing resistance to β-Lactam antibiotics, and especially to carbapenems, widely used to treat beta-lactamase producing multidrug resistant gram-negative bacterial infections has limited their therapeutic options and currently represents a major concern. Microbial natural products have been for decades a successful source of new drugs, and after the failure of synthetic libraries to deliver novel antibiotics, they represent today an untapped resource for the discovery of novel compounds.
In this regard, whereas high throughput screening (HTS) of natural product extract collections has been a very successful tool, the implementation and validation of new alternatives to improve the quality and performance of their screening are still required. We present a new approach based on a combined whole cell assay (fluorescence and absorbance) that can be applied to discover new chemical entities with broad spectrum antibacterial activity against Gram-negative human pathogens. The approach has been validated by establishing the experimental high-throughput screening conditions (HTS) to identify from Medina’s NPs library, extracts enhancing the activity of the carbapenem imipenem. We describe the performance of the assay using sublethal doses of imipenem and the pilot screening of 10.000 microbial natural products extracts to identify new potentiators of its activity. The methodology developed may be applied to different microorganisms and used to search enhancers of different antimicrobial agents challenged in clinic by the emergence of antibiotic resistance.

Type of Paper: Article
Title: Rational Design of Novel Ligands for the Aryl Hydrocarbon Receptor Using Targeted-Based Screenings
Authors: S.K. Kolluri and W.H. Bisson
Affiliation: Environmental and Molecular Toxicology, Oregon State University, ALS 1011, Corvallis, OR, 97331, USA; E-Mails: Siva.Kolluri@oregonstate.edu (S.K.K.); bissonw@science.oregonstate.edu (W.H.B.)
Abstract: The aryl hydrocarbon receptor (AhR) is a ligand activated member of the basic helix-loop-helix (BhLH) family of transcription factors. The AhR is activated by a variety of compounds, both synthetic and natural, including halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their biological activity. The AhR is a cytosolic transcription factor bound to several co-chaperones. Upon ligand binding, the AhR translocates from the cytoplasm to the nucleus and regulates genes, including several drug metabolizing enzymes that can influence the therapeutic activity of a number of compounds. The AhR regulates proliferation and differentiation of cells. In addition, the AhR induces immunosuppressive regulatory T cells with therapeutic implications in hyper-immune disorders. The role of the AhR has been studied in cancer, inflammatory diseases, allergies and tissue regeneration. Up to now, the AhR Ligand Binding Domain remains experimentally unresolved. Hence, to find novel ligands targeting the AhR either cell-based screenings or in silico computer-aided drug design (CADD) techniques have been used. Successful applications in finding novel agonists, selective modulators (sAhRM) and full antagonists of the AhR will be described. Recent mechanistic studies using computational molecular simulations on the AhR models will be reported. The results obtained demonstrate that in the absence of experimentally resolved structures, targeted screenings using cell-based assays and computational chemical genomics techniques remain important tools for the discovery of novel small organic molecule therapeutics.

Last update: 19 February 2014

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