Supersecondary Structures and Fragment Libraries

2019 ◽  
pp. 283-295
Author(s):  
Raphael Trevizani ◽  
Fábio Lima Custódio
Keyword(s):  
Fragment Libraries

Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries

2021 ◽  
Author(s):  
David J. Hamilton ◽  
Tom Dekker ◽  
Hanna F. Klein ◽  
Guido V. Janssen ◽  
Maikel Wijtmans ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Property Analysis ◽  
Fragment Libraries ◽  
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 A drug discovery-oriented non-invasive protocol for protein crystal cryoprotection by dehydration, with application for crystallization screening.

2021 ◽  
Author(s):  
Dom Bellini
Keyword(s):  
Drug Discovery ◽  
Ligand Binding ◽  
Protein Crystal ◽  
Macromolecular Crystallography ◽  
X Ray ◽  
Water Fraction ◽  
Non Invasive ◽  
Vapour Diffusion ◽  
Large Compound ◽  
Fragment Libraries

In X-ray macromolecular crystallography, cryoprotection of crystals mounted on harvesting loops is achieved when the water in the sample solvent transitions to vitreous ice before crystalline ice forms. This is achieved by rapid cooling in liquid nitrogen or propane. Protocols for protein crystal cryoprotection are based on either increasing environmental pressure or reducing the water fraction in the solvent. This study presents a new protocol for cryoprotecting crystals. It is based on vapour diffusion dehydration of the crystal drop to reduce the water fraction in the solvent by adding a highly concentrated salt solution, 13 M potassium formate (KF13), directly to the reservoir. Cryoprotection by the KF13 protocol is non-invasive to the crystal, high throughput, not labour intensive, can benefit diffraction resolution and ligand binding, and is very useful in cases with high redundancy such as drug discovery projects which utilize very large compound or fragment libraries. Moreover, an application of KF13 to discover new crystal hits from clear drops of equilibrated crystallization screening plates is also shown.

scholarly journals How Size Matters: Designing Diverse Fragment Libraries for Novel Drug Discovery

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 107
Author(s):  
Yun Shi ◽  
Mark von Itzstein
Keyword(s):  
Drug Discovery ◽  
Chemical Space ◽  
Structural Diversity ◽  
Optimal Size ◽  
Zinc Database ◽  
Fragment Library ◽  
Size Diversity ◽  
Efficient Exploration ◽  
Novel Drug ◽  
Fragment Libraries

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for both new and established therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. In order to construct a library that maximises the chances of discovering novel chemical matter, a large number of fragments with sufficient structural diversity are often sought. However, the exact diversity of a certain collection of fragments remains elusive, which hinders direct comparisons among different selections of fragments. Building upon structural fingerprints that are commonly utilised in cheminformatics, we herein introduced quantitative measures for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database and filtered by physicochemical properties, after which they were subject to selections with library sizes ranging from 100 to 100,000 compounds. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results suggested the existence of an optimal size for structural diversity and demonstrated that such quantitative measures can guide the design of diverse fragment libraries under various circumstances

scholarly journals Rapid, low-input, low-bias construction of shotgun fragment libraries by high-density in vitro transposition

2010 ◽  
Vol 11 (12) ◽  
pp. R119 ◽  
Author(s):  
Andrew Adey ◽  
Hilary G Morrison ◽  
Asan (no last name) ◽  
Xu Xun ◽  
Jacob O Kitzman ◽  
...  
Keyword(s):  
High Density ◽  
Low Input ◽  
Fragment Libraries ◽  
In Vitro Transposition

scholarly journals Label-Free Primary Screening and Affinity Ranking of Fragment Libraries Using Parallel Analysis of Protein Panels

2008 ◽  
Vol 13 (3) ◽  
pp. 202-209 ◽  
Author(s):  
Markku D. Hämäläinen ◽  
Andrei Zhukov ◽  
Maria Ivarsson ◽  
Tomas Fex ◽  
Johan Gottfries ◽  
...  
Keyword(s):  
Binding Site ◽  
Parallel Analysis ◽  
Label Free ◽  
Glutathione S Transferase ◽  
Chip Surface ◽  
Fragment Screening ◽  
Fragment Library ◽  
Direct Binding ◽  
Resonance Detection ◽  
Fragment Libraries

The authors present fragment screening data obtained using a label-free parallel analysis approach where the binding of fragment library compounds to 4 different target proteins can be screened simultaneously using surface plasmon resonance detection. They suggest this method as a first step in fragment screening to identify and select binders, reducing the demanding requirements on subsequent X-ray or nuclear magnetic resonance studies, and as a valuable “clean-up” tool to eliminate unwanted promiscuous binders from libraries. A small directed fragment library of known thrombin binders and a general 500-compound fragment library were used in this study. Thrombin, blocked thrombin, carbonic anhydrase, and glutathione-S-transferase were immobilized on the sensor chip surface, and the direct binding of the fragments was studied in real time. Only 12 µg of each protein is needed for screening of a 3000-compound fragment library. For screening, a binding site-blocked target as reference facilitates the identification of binding site-selective hits and the signals from other reference proteins for the elimination of false positives. The scope and limitations of this screening approach are discussed for both target-directed and general fragment libraries. ( Journal of Biomolecular Screening 2008:202-209)

scholarly journals Parallel Screening of Low Molecular Weight Fragment Libraries

2012 ◽  
Vol 18 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Jerome Wielens ◽  
Stephen J. Headey ◽  
David I. Rhodes ◽  
Roger J. Mulder ◽  
Olan Dolezal ◽  
...  
Keyword(s):  
Screening Methods ◽  
Resonance Spectroscopy ◽  
Lead Discovery ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Lead Compounds ◽  
Preliminary Identification ◽  
Std Nmr ◽  
Fragment Libraries

Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.

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