scholarly journals A carbohydrate-derived trifunctional scaffold for medicinal chemistry library synthesis

2018 ◽  
Vol 7 (2) ◽  
pp. 135-144
Author(s):  
Diana I. S. P. Resende ◽  
Amalia M. Estévez ◽  
Andre M. Alker ◽  
Rainer E. Martin ◽  
Hans Peter Wessel
Keyword(s):  
Drug Discovery ◽  
Carboxylic Acid ◽  
Sodium Azide ◽  
Secondary Alcohol ◽  
Library Synthesis ◽  
X Ray ◽  
X Ray Crystallography ◽  
Compound Libraries ◽  
Ready Access ◽  
Epoxide Formation

For the generation of compound libraries for drug discovery a central scaffold containing three exit vectors with defined chirality was devised starting from commercially available tri-O-acetyl-glucal. Surprisingly, the reaction of a 4-O-mesylate with sodium azide did not lead to the expected 4-azido-4-deoxy derivative but to a 3-azido-3-deoxy regioisomer via intermediate epoxide formation. The absolute stereochemical configuration of the final tetrahydropyran building block was proven by X-ray crystallography. This scaffold endowed with a carboxylic acid, a secondary alcohol, and an azide functionality may be connected to a DNA tag at any of the three distinct exit vectors, thus providing ready access to several different compound libraries. 

scholarly journals Protein X-ray Crystallography and Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1030 ◽  
Author(s):  
Laurent Maveyraud ◽  
Lionel Mourey
Keyword(s):  
Drug Discovery ◽  
Structural Information ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
X Ray ◽  
Drug Candidates ◽  
X Ray Crystallography ◽  
Compound Libraries ◽  
Fragment Library ◽  
Invaluable Tool

With the advent of structural biology in the drug discovery process, medicinal chemists gained the opportunity to use detailed structural information in order to progress screening hits into leads or drug candidates. X-ray crystallography has proven to be an invaluable tool in this respect, as it is able to provide exquisitely comprehensive structural information about the interaction of a ligand with a pharmacological target. As fragment-based drug discovery emerged in the recent years, X-ray crystallography has also become a powerful screening technology, able to provide structural information on complexes involving low-molecular weight compounds, despite weak binding affinities. Given the low numbers of compounds needed in a fragment library, compared to the hundreds of thousand usually present in drug-like compound libraries, it now becomes feasible to screen a whole fragment library using X-ray crystallography, providing a wealth of structural details that will fuel the fragment to drug process. Here, we review theoretical and practical aspects as well as the pros and cons of using X-ray crystallography in the drug discovery process.

scholarly journals Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245013
Author(s):  
Sixue Zhang ◽  
Atefeh Garzan ◽  
Nicole Haese ◽  
Robert Bostwick ◽  
Yohanka Martinez-Gzegozewska ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Carboxylic Acid ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Chikungunya Virus ◽  
X Ray ◽  
X Ray Crystallography ◽  
Small Molecule Drugs ◽  
Fragment Library ◽  
Fragment Based Drug Discovery

The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 μM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential pan-antiviral activity.

Protein X-ray Crystallography in Drug Discovery

2005 ◽  
pp. 373-455 ◽  
Author(s):  
Peter Nollert ◽  
Michael D. Feese ◽  
Bart L. Staker ◽  
Hidong Kim
Keyword(s):  
Drug Discovery ◽  
X Ray ◽  
X Ray Crystallography ◽  
Protein X

scholarly journals X-ray crystallography over the past decade for novel drug discovery – where are we heading next?

2015 ◽  
Vol 10 (9) ◽  
pp. 975-989 ◽  
Author(s):  
Heping Zheng ◽  
Katarzyna B Handing ◽  
Matthew D Zimmerman ◽  
Ivan G Shabalin ◽  
Steven C Almo ◽  
...  
Keyword(s):  
Drug Discovery ◽  
X Ray ◽  
X Ray Crystallography ◽  
The Past ◽  
Novel Drug

scholarly journals Identification of novel allosteric inhibitors through fragment-based drug discovery and X-ray crystallography  

2015 ◽  
Vol 71 (a1) ◽  
pp. s38-s38
Author(s):  
Puja Pathuri ◽  
Susanne M. Saalau-Bethell ◽  
Andrew J. Woodhead ◽  
Valerio Berdini ◽  
Maria G. Carr ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Allosteric Inhibitors ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Based Drug Discovery

scholarly journals Cocktailed fragment screening by X-ray crystallography of the antibacterial target undecaprenyl pyrophosphate synthase from Acinetobacter baumannii

2020 ◽  
Vol 76 (1) ◽  
pp. 40-46
Author(s):  
James H. Thorpe ◽  
Ian D. Wall ◽  
Robert H. Sinnamon ◽  
Amy N. Taylor ◽  
Robert A. Stavenger
Keyword(s):  
Drug Discovery ◽  
Acinetobacter Baumannii ◽  
Structural Data ◽  
X Ray ◽  
Traditional Medicines ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Binding Pockets ◽  
Antibacterial Target ◽  
Robustness Check

Direct soaking of protein crystals with small-molecule fragments grouped into complementary clusters is a useful technique when assessing the potential of a new crystal system to support structure-guided drug discovery. It provides a robustness check prior to any extensive crystal screening, a double check for assay binding cutoffs and structural data for binding pockets that may or may not be picked out in assay measurements. The structural output from this technique for three novel fragment molecules identified to bind to the antibacterial target Acinetobacter baumannii undecaprenyl pyrophosphate synthase are reported, and the different physicochemical requirements of a successful antibiotic are compared with traditional medicines.

scholarly journals Mass spectrometry for fragment screening

2017 ◽  
Vol 61 (5) ◽  
pp. 465-473 ◽  
Author(s):  
Daniel Shiu-Hin Chan ◽  
Andrew J. Whitehouse ◽  
Anthony G. Coyne ◽  
Chris Abell
Keyword(s):  
Drug Discovery ◽  
High Sensitivity ◽  
Titration Calorimetry ◽  
Label Free ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Differential Scanning Fluorimetry ◽  
Biophysical Techniques

Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography. In this context, MS is a relatively underutilized technique in fragment screening for drug discovery. MS-based techniques have the advantage of high sensitivity, low sample consumption and being label-free. This review highlights recent examples of the emerging use of MS-based techniques in fragment screening.

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