Fragment-based drug discovery and its application to challenging drug targets

2017 ◽  
Vol 61 (5) ◽  
pp. 475-484 ◽  
Author(s):  
Amanda J. Price ◽  
Steven Howard ◽  
Benjamin D. Cons
Keyword(s):  
Molecular Weight ◽  
Drug Discovery ◽  
Drug Targets ◽  
Structural Information ◽  
New Drugs ◽  
Low Molecular Weight ◽  
Related Factor ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Based Drug Discovery

Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein–protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2.

Counting on Fragment Based Drug Design Approach for Drug Discovery

2019 ◽  
Vol 18 (27) ◽  
pp. 2284-2293 ◽  
Author(s):  
Aanchal Kashyap ◽  
Pankaj Kumar Singh ◽  
Om Silakari
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Structural Information ◽  
Binding Mode ◽  
New Drugs ◽  
Design Approach ◽  
X Ray ◽  
X Ray Crystallography ◽  
Success Stories

Fragment based drug design (FBDD) is a structure guided ligand design approach used in the process of drug discovery. It involves identification of low molecular weight fragments as hits followed by determination of their binding mode using X-ray crystallography and/or NMR spectroscopy. X-ray protein crystallography is one of the most sensitive biophysical methods used for screening and is least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. The retrieved binding information facilitates the optimization of fragments into drug like molecules. These identified molecules bind efficiently with the target proteins and form high quality binding interactions. Fragment-based screening using X-ray crystallography is, therefore, an efficient method for identifying binding hotspots on proteins that can be further exploited by chemists and biologists for the discovery of new drugs. The recent advancements in FBDD technique are illustrated in this review along with recently published success stories of FBDD technique in drug discovery.

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 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.

Perspectives on Fragment-based Drug Discovery: A Strategy Applicable to Diverse Targets

2021 ◽  
Vol 21 ◽  
Author(s):  
Qingxin Li ◽  
Congbao Kang
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Nmr Spectroscopy ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Hit Rate ◽  
Powerful Strategy ◽  
Fragment Based Drug Discovery

: Fragment-based drug discovery (FBDD) is a strategy to develop potent lead molecules and is frequently used in drug discovery projects of the pharmaceutical industry. This method starts from identifying a small-molecule fragment which usually binds weakly to the target and follows with a hit-to-lead step in which the fragment is grown into potent molecules that bind tightly to the target to affect its function. Quite a few drugs and compounds in clinical trials are developed using this approach, making FBDD a powerful strategy in drug discovery. FBDD can be applied to multiple targets and the hit rate in screening can be used in target druggability assessment. In this mini-review, we provide a summary for the development of FBDD. In addition to giving a brief summary of the methods used in fragment screening, we highlight some methods that are critical in the fragment growth. Biophysical methods and carefully chemical modification of the fragments are the key elements in FBDD. We show several strategies that can be utilized in FBDD. We emphasize that NMR spectroscopy such as 19F-NMR and 1H-15N-HSQC experiment and X-ray crystallography are important in FBDD due to their roles in fragment screening and understanding the binding modes of the fragment hits, which provides a strategy for fragment growth.

Crystallization of low-molecular-weight organic compounds for X-ray crystallography

1989 ◽  
Vol 22 (4) ◽  
pp. 340-344 ◽  
Author(s):  
P. van der Sluis ◽  
A. M. F. Hezemans ◽  
J. Kroon
Keyword(s):  
Molecular Weight ◽  
Vapor Phase ◽  
Vecuronium Bromide ◽  
Low Molecular Weight ◽  
Batch Crystallization ◽  
X Ray ◽  
Phase Diffusion ◽  
Liquid Diffusion ◽  
X Ray Crystallography

General strategies are described to obtain crystals of low-molecular-weight compounds suitable for X-ray structure determination. A survey is given of a variety of crystallization techniques together with their advantages and drawbacks, illustrated by experiences with notoriously crystallization-resisting compounds. The methods discussed range from preliminary investigations using evaporation, batch crystallization and liquid–liquid diffusion methods, via the most frequently used methods such as sitting-drop vapor-phase diffusion and change of temperature, to methods such as gel crystallization, sublimation and solidification. The most successful method appears to be the sitting-drop vapor-phase diffusion. Complete crystallization routes are described, taking into account the results of preliminary investigations. The hard-to-crystallize vecuronium bromide is presented as a case study.

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