Analysis of the productivity of DNA encoded libraries

MedChemComm ◽  
2016 ◽  
Vol 7 (7) ◽  
pp. 1323-1331 ◽  
Author(s):  
Oliv Eidam ◽  
Alexander L. Satz
Keyword(s):  
Physical Properties ◽  
Structural Diversity ◽  
Library Size ◽  
Protein Targets

Analysis of physical properties and structural diversity of 57 molecules derived from screening 5–16 DNA encoded libraries against two protein targets. DNA encoded library size is not predictive of productivity.

Structural Diversity and Physical Properties of Paramagnetic Molecular Conductors Based on Bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) and the Tris(chloranilato)ferrate(III) Complex

2014 ◽  
Vol 53 (13) ◽  
pp. 7028-7039 ◽  
Author(s):  
Matteo Atzori ◽  
Flavia Pop ◽  
Pascale Auban-Senzier ◽  
Carlos J. Gómez-García ◽  
Enric Canadell ◽  
...  
Keyword(s):  
Physical Properties ◽  
Structural Diversity ◽  
Molecular Conductors

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Warren R.J.D. Galloway ◽  
David R. Spring
Keyword(s):  
Small Molecule ◽  
Structural Diversity ◽  
Library Size ◽  
Diversity Oriented Synthesis ◽  
Biological Targets ◽  
Small Molecule Screening ◽  
Chemistry Research ◽  
Large Numbers ◽  
Small Molecule Libraries ◽  
Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

scholarly journals Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

Syntheses, structural diversity and photo-physical properties of copper(I) and silver(I) coordination polymers based on the pyridine-4-amidoxime ligand

Polyhedron ◽  
2013 ◽  
Vol 65 ◽  
pp. 252-261 ◽  
Author(s):  
Madhusudan Nandy ◽  
Sambuddha Banerjee ◽  
Corrado Rizzoli ◽  
Ennio Zangrando ◽  
Aline Nonat ◽  
...  
Keyword(s):  
Physical Properties ◽  
Coordination Polymers ◽  
Structural Diversity

scholarly journals How Size Matters: Diversity for Fragment Library Design

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2838 ◽  
Author(s):  
Yun Shi ◽  
Mark von Itzstein
Keyword(s):  
Chemical Space ◽  
Structural Diversity ◽  
Optimal Size ◽  
Library Size ◽  
Quantitative Metrics ◽  
Zinc Database ◽  
Fragment Library ◽  
Size Diversity ◽  
Efficient Exploration ◽  
Fragment Libraries

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various 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. A diverse set of fragments is required to maximize the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

scholarly journals How Size Matters: Diversity for Fragment Library Design

2019 ◽  
Author(s):  
Yun Shi ◽  
Mark von Itzstein
Keyword(s):  
Chemical Space ◽  
Structural Diversity ◽  
Optimal Size ◽  
Library Size ◽  
Quantitative Metrics ◽  
Zinc Database ◽  
Fragment Library ◽  
Size Diversity ◽  
Efficient Exploration ◽  
Fragment Libraries

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW &lt; 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. A diverse set of fragments is required to maximise the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

scholarly journals Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library

2020 ◽  
Vol 117 (29) ◽  
pp. 16782-16789 ◽  
Author(s):  
Surendra Dawadi ◽  
Nicholas Simmons ◽  
Gabriella Miklossy ◽  
Kurt M. Bohren ◽  
John C. Faver ◽  
...  
Keyword(s):  
Structural Diversity ◽  
Catalytic Triad ◽  
Combinatorial Synthesis ◽  
Thrombin Inhibitors ◽  
Library Design ◽  
Chemical Library ◽  
Dna Oligomers ◽  
Protein Targets ◽  
Chemical Libraries ◽  
Selection Of

DNA-encoded chemical libraries are collections of compounds individually coupled to unique DNA tags serving as amplifiable identification barcodes. By bridging split-and-pool combinatorial synthesis with the ligation of unique encoding DNA oligomers, million- to billion-member libraries can be synthesized for use in hundreds of healthcare target screens. Although structural diversity and desirable molecular property ranges generally guide DNA-encoded chemical library design, recent reports have highlighted the utility of focused DNA-encoded chemical libraries that are structurally biased for a class of protein targets. Herein, a protease-focused DNA-encoded chemical library was designed that utilizes chemotypes known to engage conserved catalytic protease residues. The three-cycle library features functional moieties such as guanidine, which interacts strongly with aspartate of the protease catalytic triad, as well as mild electrophiles such as sulfonamide, urea, and carbamate. We developed a DNA-compatible method for guanidinylation of amines and reduction of nitriles. Employing these optimized reactions, we constructed a 9.8-million-membered DNA-encoded chemical library. Affinity selection of the library with thrombin, a common protease, revealed a number of enriched features which ultimately led to the discovery of a 1 nM inhibitor of thrombin. Thus, structurally focused DNA-encoded chemical libraries have tremendous potential to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g., proteases) with essential functions in infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2) and relevant healthcare conditions (e.g., male contraception).

Structural Diversity Attributed by Aza-Diels-Alder Reaction in Synthesis of Diverse Quinoline Scaffolds

2019 ◽  
Vol 23 (8) ◽  
pp. 920-958 ◽  
Author(s):  
Dharmender Singh ◽  
Vipin Kumar ◽  
Chandi C. Malakar ◽  
Virender Singh
Keyword(s):  
Structural Diversity ◽  
Alder Reaction ◽  
Diels Alder ◽  
Protein Targets ◽  
Feasible Method ◽  
Diels Alder Reaction ◽  
Scaffold Diversity ◽  
Synthetic Chemist

In recent years, the synthesis of quinoline scaffold using various methodological devices has attracted considerable attention in synthetic chemist community. The most feasible method to serve this purpose is Aza-Diels-Alder reaction which provides flexibility and diversity in the synthesis of quinoline decorated with different functionalities over the scaffold. Diversity in this functionality improvises the susceptibility of the quinoline scaffold for various protein targets. This review encompasses multifactorial aspects of Aza-Diels-Alder reaction as well as provides insights into the synthetic schemes for quinoline scaffold.

Towards Fluorinated Ruddlesden-Popper Perovskites with Enhanced Physical Properties: A Study on (3-FC6H4CH2CH2NH3)2PbI4 Single Crystals

2021 ◽  
Author(s):  
Xiangxin Tian ◽  
Zhaoxing Hu ◽  
Zeliang Gao ◽  
Yongzhuan Zhang ◽  
Chuanming Li ◽  
...  
Keyword(s):  
Physical Properties ◽  
Single Crystals ◽  
Molecular Design ◽  
Structural Diversity ◽  
Environmental Stability ◽  
Two Dimensional ◽  
Design Strategies ◽  
Rational Molecular Design ◽  
Related Application

Quasi two-dimensional Ruddlesden-Popper perovskites (RPPs) have drawn unprecedented research interests for their superior long-term environmental stability, abundant structural diversity, and favorable performance in energy-related application scenario. Rational molecular design strategies,...

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