scholarly journals The Light and Dark Sides of Virtual Screening: What Is There to Know?

2019 ◽  
Vol 20 (6) ◽  
pp. 1375 ◽  
Author(s):  
Aleix Gimeno ◽  
María Ojeda-Montes ◽  
Sarah Tomás-Hernández ◽  
Adrià Cereto-Massagué ◽  
Raúl Beltrán-Debón ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Small Molecules ◽  
Bioactive Compounds ◽  
In Silico ◽  
Research Team ◽  
Computational Tools ◽  
Private And Public ◽  
New Methodologies ◽  
Experienced Researcher

Virtual screening consists of using computational tools to predict potentially bioactive compounds from files containing large libraries of small molecules. Virtual screening is becoming increasingly popular in the field of drug discovery as in silico techniques are continuously being developed, improved, and made available. As most of these techniques are easy to use, both private and public organizations apply virtual screening methodologies to save resources in the laboratory. However, it is often the case that the techniques implemented in virtual screening workflows are restricted to those that the research team knows. Moreover, although the software is often easy to use, each methodology has a series of drawbacks that should be avoided so that false results or artifacts are not produced. Here, we review the most common methodologies used in virtual screening workflows in order to both introduce the inexperienced researcher to new methodologies and advise the experienced researcher on how to prevent common mistakes and the improper usage of virtual screening methodologies.

scholarly journals A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments

2019 ◽  
Vol 20 (18) ◽  
pp. 4648 ◽  
Author(s):  
Nathalie Lagarde ◽  
Elodie Goldwaser ◽  
Tania Pencheva ◽  
Dessislava Jereva ◽  
Ilza Pajeva ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Web Service ◽  
Molecular Mechanics ◽  
In Silico ◽  
Chemical Biology ◽  
In Silico Screening ◽  
Web Based ◽  
Screening Experiments ◽  
The Web

Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web service MTiOpenScreen), and molecular mechanics optimization (via the web service AMMOS2 [Automatic Molecular Mechanics Optimization for in silico Screening]). The online tools FAF-Drugs4, MTiOpenScreen, and AMMOS2 are implemented in the freely accessible RPBS (Ressource Parisienne en Bioinformatique Structurale) platform. The proposed protocol allows users to screen thousands of small molecules and to download the top 1500 docked molecules that can be further processed online. Users can then decide to purchase a small list of compounds for in vitro validation. To demonstrate the potential of this online-based protocol, we performed virtual screening experiments of 4574 approved drugs against three cancer targets. The results were analyzed in the light of published drugs that have already been repositioned on these targets. We show that our protocol is able to identify active drugs within the top-ranked compounds. The web-based protocol is user-friendly and can successfully guide the identification of new promising molecules for chemical biology and drug discovery purposes.

Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies

2016 ◽  
Vol 35 (9) ◽  
pp. 1899-1915 ◽  
Author(s):  
Ramin Ekhteiari Salmas ◽  
Ayhan Unlu ◽  
Muhammet Bektaş ◽  
Mine Yurtsever ◽  
Mert Mestanoglu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecules ◽  
In Silico ◽  
In Vitro Studies ◽  
Parp 1

scholarly journals Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities

2020 ◽  
Vol 5 ◽  
pp. 169
Author(s):  
Gilda Padalino ◽  
Iain W. Chalmers ◽  
Andrea Brancale ◽  
Karl F. Hoffmann
Keyword(s):  
Virtual Screening ◽  
Small Molecules ◽  
Adult Worm ◽  
In Silico ◽  
Egg Production ◽  
Homology Modelling ◽  
Homology Model ◽  
Biological Data ◽  
Significant Activity ◽  
Starting Point

Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity.   Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds’ activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1’s homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.

scholarly journals Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities

2020 ◽  
Vol 5 ◽  
pp. 169
Author(s):  
Gilda Padalino ◽  
Iain W. Chalmers ◽  
Andrea Brancale ◽  
Karl F. Hoffmann
Keyword(s):  
Virtual Screening ◽  
Small Molecules ◽  
Adult Worm ◽  
In Silico ◽  
Egg Production ◽  
Homology Modelling ◽  
Homology Model ◽  
Biological Data ◽  
Significant Activity ◽  
Starting Point

Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity.   Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds’ activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1’s homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.

scholarly journals Prospective virtual screening with Ultrafast Shape Recognition: the identification of novel inhibitors of arylamine N -acetyltransferases

2009 ◽  
Vol 7 (43) ◽  
pp. 335-342 ◽  
Author(s):  
Pedro J. Ballester ◽  
Isaac Westwood ◽  
Nicola Laurieri ◽  
Edith Sim ◽  
W. Graham Richards
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Small Molecules ◽  
Shape Recognition ◽  
Molecular Targets ◽  
Efficient Manner ◽  
Hit Rate ◽  
Shape Complementarity ◽  
Outstanding Result ◽  
Novel Structures

There is currently a shortage of chemical molecules that can be used as bioactive probes to study molecular targets and potentially as starting points for drug discovery. One inexpensive way to address this problem is to use computational methods to screen a comprehensive database of small molecules to discover novel structures that could lead to alternative and better bioactive probes. Despite that pleasing logic the results have been somewhat mixed. Here we describe a virtual screening technique based on ligand–receptor shape complementarity, Ultrafast Shape Recognition (USR). USR is specifically applied to identify novel inhibitors of arylamine N -acetyltransferases by computationally screening almost 700 million molecular conformers in a time- and resource-efficient manner. A small number of the predicted active compounds were purchased and tested obtaining a confirmed hit rate of 40 per cent which is an outstanding result for a prospective virtual screening.

scholarly journals InterLig: improved ligand-based virtual screening using topologically independent structural alignments

2020 ◽  
Vol 36 (10) ◽  
pp. 3266-3267
Author(s):  
Claudio Mirabello ◽  
Björn Wallner
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Small Molecules ◽  
Supplementary Information ◽  
Scaffold Hopping ◽  
Supplementary Data ◽  
Protein Target ◽  
The Past ◽  
3D Methods ◽  
Structural Alignments

Abstract Motivation In the past few years, drug discovery processes have been relying more and more on computational methods to sift out the most promising molecules before time and resources are spent to test them in experimental settings. Whenever the protein target of a given disease is not known, it becomes fundamental to have accurate methods for ligand-based virtual screening, which compares known active molecules against vast libraries of candidate compounds. Recently, 3D-based similarity methods have been developed that are capable of scaffold hopping and to superimpose matching molecules. Results Here, we present InterLig, a new method for the comparison and superposition of small molecules using topologically independent alignments of atoms. We test InterLig on a standard benchmark and show that it compares favorably to the best currently available 3D methods. Availability and implementation The program is available from http://wallnerlab.org/InterLig. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals In Silico Strategies in Tuberculosis Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 665
Author(s):  
Stephani Joy Y. Macalino ◽  
Junie B. Billones ◽  
Voltaire G. Organo ◽  
Maria Constancia O. Carrillo
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
In Silico ◽  
Global Public Health ◽  
Computational Tools ◽  
Protein Targets ◽  
Tb Treatment ◽  
Discovery Research ◽  
Poor Patient Compliance ◽  
Drug Discovery Research

Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018. While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs. Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic. In silico strategies can be applied at multiple stages of the drug discovery paradigm to expedite the identification of novel anti-TB therapeutics. In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional biochemical methods. We will also highlight the strengths and points of improvement in in silico TB drug discovery research, as well as possible future perspectives in this field.

scholarly journals In silico virtual screening approaches for anti-viral drug discovery

2012 ◽  
Vol 9 (3) ◽  
pp. e219-e225 ◽  
Author(s):  
Manuela S. Murgueitio ◽  
Marcel Bermudez ◽  
Jérémie Mortier ◽  
Gerhard Wolber
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
In Silico ◽  
Screening Approaches

scholarly journals Hapten engineering: Raising antibodies against the smallest of small molecules

2003 ◽  
Vol 25 (6) ◽  
pp. 35-37
Author(s):  
Andy Porter
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Small Molecules ◽  
Research Team ◽  
Antibody Engineering ◽  
Therapeutic Antibody ◽  
Protein Targets ◽  
Potential Success ◽  
Important Field ◽  
First Time

In recent years, antibody engineering has become one of the most important and most productive routes to drug discovery. It is now widely accepted that this approach can reduce development times and increase potential success, compared with classical drug development. Until recently, the isolation and production of therapeutic-antibody products has been concentrated on larger, protein targets. A research team at Haptogen has now overcome the significant technical difficulties that have been associated with raising antibodies to the smallest of small molecules — bioactive haptens — and, for the first time, anti-hapten therapeutics can be realized. Here, we outline our pioneering approach to antibody engineering and present the results of early work in the important field of anti-infective therapy.

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