scholarly journals Crystallographic Fragment-Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease

2013 ◽  
Vol 83 (2) ◽  
pp. 141-148 ◽  
Author(s):  
Theresa Tiefenbrunn ◽  
Stefano Forli ◽  
Meaghan Happer ◽  
Ana Gonzalez ◽  
Yingssu Tsai ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Hiv Protease ◽  
Fragment Library ◽  
Fragment Based Drug Discovery

scholarly journals Fragment Library of Natural Products and Compound Databases for Drug Discovery

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1518 ◽  
Author(s):  
Ana L. Chávez-Hernández ◽  
Norberto Sánchez-Cruz ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Synthetic Compounds ◽  
Drug Candidates ◽  
Compound Libraries ◽  
Chemical Database ◽  
Fragment Library ◽  
Further Development ◽  
Fragment Libraries ◽  
Fragment Based Drug Discovery

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.

scholarly journals Access to 3D Alicyclic Amine-Containing Fragments through Transannular C–H Arylation

Synlett ◽  
2019 ◽  
Vol 30 (04) ◽  
pp. 417-422 ◽  
Author(s):  
Melissa Lee ◽  
Ashley Adams ◽  
Philip Cox ◽  
Melanie Sanford
Keyword(s):  
Drug Discovery ◽  
Microwave Heating ◽  
Reaction Times ◽  
Rule Of Three ◽  
New Approaches ◽  
Fragment Library ◽  
Directing Group ◽  
Fragment Based Drug Discovery

In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp3)–H arylation of alicyclic amines for applications in fragment-based drug discovery (FBDD). We apply this method to the synthesis of a series of 6-arylated 3-azabicyclo[3.1.0]hexanes that are rule-of-three compliant fragments. Several modifications were made to the Pd-catalyzed C–H arylation method to enhance its utility in fragment synthesis. These include the use of microwave heating to shorten reaction times to under 1 h and the development of new approaches for directing group cleavage. Finally, we demonstrate that this fragment library falls within desirable physicochemical space for FBDD applications.

scholarly journals Large Scale Meta-Analysis of Fragment-Based Screening Campaigns

2014 ◽  
Vol 20 (5) ◽  
pp. 588-596 ◽  
Author(s):  
Peter S. Kutchukian ◽  
Anne Mai Wassermann ◽  
Mika K. Lindvall ◽  
S. Kirk Wright ◽  
Johannes Ottl ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Large Scale ◽  
Meta Analysis ◽  
Screening Strategy ◽  
Simple Rule ◽  
Specific Target ◽  
Rule Of Thumb ◽  
Fragment Screening ◽  
Fragment Library ◽  
Fragment Based Drug Discovery

A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment “hits.” However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits.

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.

scholarly journals Structure-guided, target-based drug discovery – exploiting genome information from HIV to mycobacterial infections

2016 ◽  
Vol 62 (3) ◽  
pp. 262-272
Author(s):  
Sony Malhotra ◽  
Sherine E. Thomas ◽  
Bernardo Ochoa Montano ◽  
Tom L. Blundell
Keyword(s):  
Drug Discovery ◽  
Binding Sites ◽  
Target Identification ◽  
Hiv Protease ◽  
Inhibitor Binding ◽  
Mycobacterial Infections ◽  
Lead Compounds ◽  
Lead Optimisation ◽  
Genome Information ◽  
Fragment Based Drug Discovery

The use of protein crystallography in structure-guided drug discovery allows identification of potential inhibitor-binding sites and optimisation of interactions of hits and lead compounds with a target protein. An early example of this approach was the use of the structure of HIV protease in designing AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design. Here, we discuss the use of structure-guided target identification and lead optimisation using fragment-based approaches in the development of new antimicrobials for mycobacterial infections.

Fragments: where are we now?

2020 ◽  
Vol 48 (1) ◽  
pp. 271-280 ◽  
Author(s):  
James Osborne ◽  
Stanislava Panova ◽  
Magdalini Rapti ◽  
Tatsuya Urushima ◽  
Harren Jhoti
Keyword(s):  
Drug Discovery ◽  
Drug Administration ◽  
Clinical Studies ◽  
Food And Drug Administration ◽  
Library Design ◽  
Lead Optimisation ◽  
Fragment Library ◽  
The Future ◽  
Fragment Based Drug Discovery

Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.

scholarly journals Applications of Solution NMR in Drug Discovery

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 576
Author(s):  
Li Shi ◽  
Naixia Zhang
Keyword(s):  
Drug Discovery ◽  
Working Mechanism ◽  
Protein Protein Interaction ◽  
Promising Tool ◽  
Fragment Library ◽  
Nmr Techniques ◽  
Approved Drugs ◽  
Solution Nuclear Magnetic Resonance ◽  
Fda Approved Drugs ◽  
Fragment Based Drug Discovery

During the past decades, solution nuclear magnetic resonance (NMR) spectroscopy has demonstrated itself as a promising tool in drug discovery. Especially, fragment-based drug discovery (FBDD) has benefited a lot from the NMR development. Multiple candidate compounds and FDA-approved drugs derived from FBDD have been developed with the assistance of NMR techniques. NMR has broad applications in different stages of the FBDD process, which includes fragment library construction, hit generation and validation, hit-to-lead optimization and working mechanism elucidation, etc. In this manuscript, we reviewed the current progresses of NMR applications in fragment-based drug discovery, which were illustrated by multiple reported cases. Moreover, the NMR applications in protein-protein interaction (PPI) modulators development and the progress of in-cell NMR for drug discovery were also briefly summarized.

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