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 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

Metal-, and Organocatalyst-Free One-Pot Assembly of Chiral Aza-Tricyclic Molecules: Creating Six Contiguous Stereocenters from 2-D-Structures and an Amino Acid

2020 ◽  
Author(s):  
Dung Do
Keyword(s):  
Amino Acid ◽  
Chemical Space ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Chiral Molecules ◽  
One Pot ◽  
Complex Molecules ◽  
Chiral Catalyst ◽  
Chiral Complex ◽  
Free Process

<p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> Practically, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for desired reactions. As a result, developing a method that enables rapid assembly of chiral complex molecules under metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward route to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“subcatalyst”) dual role of the intermediate enhances </a><a>the coordinational proximity of the chiral substrate and catalyst</a> in the key Aza-Michael/Michael cascade resulting in a substantial steric discrimination and an excellent overall diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not present in the reaction’s initial components, which renders a chiral catalyst-free process, it is strategically produced to promote sequential self-catalyzed reactions. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules and aid for the quest to create next generation of therapeutic agents.</p>

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 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 hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

2020 ◽  
Author(s):  
Dung Do
Keyword(s):  
Chemical Space ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Chiral Molecules ◽  
One Pot ◽  
Complex Molecules ◽  
Chiral Complex ◽  
Enamine Catalysis ◽  
Daunting Challenge

<p></p><p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from <i>N</i>-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.</p><br><p></p>

Efficient exploration of chemical space by fragment-based screening

2014 ◽  
Vol 116 (2-3) ◽  
pp. 82-91 ◽  
Author(s):  
Richard J. Hall ◽  
Paul N. Mortenson ◽  
Christopher W. Murray
Keyword(s):  
Chemical Space ◽  
Efficient Exploration

scholarly journals BIOFACQUIM: A Mexican Compound Database of Natural Products

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 31 ◽  
Author(s):  
B. Pilón-Jiménez ◽  
Fernanda Saldívar-González ◽  
Bárbara Díaz-Eufracio ◽  
José Medina-Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Physicochemical Properties ◽  
Chemical Space ◽  
Structural Diversity ◽  
Proof Of Concept ◽  
Molecular Fingerprints ◽  
The Public ◽  
Compound Database

Compound databases of natural products have a major impact on drug discovery projects and other areas of research. The number of databases in the public domain with compounds with natural origins is increasing. Several countries, Brazil, France, Panama and, recently, Vietnam, have initiatives in place to construct and maintain compound databases that are representative of their diversity. In this proof-of-concept study, we discuss the first version of BIOFACQUIM, a novel compound database with natural products isolated and characterized in Mexico. We discuss its construction, curation, and a complete chemoinformatic characterization of the content and coverage in chemical space. The profile of physicochemical properties, scaffold content, and diversity, as well as structural diversity based on molecular fingerprints is reported. BIOFACQUIM is available for free.

Design of a Fragment Library that maximally represents available chemical space

2011 ◽  
Vol 25 (7) ◽  
pp. 611-620 ◽  
Author(s):  
M. N. Schulz ◽  
J. Landström ◽  
K. Bright ◽  
R. E. Hubbard
Keyword(s):  
Chemical Space ◽  
Fragment Library

The marginal cost of structural diversity of mixed uneven-aged hard maple forests

2002 ◽  
Vol 32 (4) ◽  
pp. 616-628 ◽  
Author(s):  
Shashi Kant
Keyword(s):  
Growth Model ◽  
Acer Saccharum ◽  
Marginal Cost ◽  
Structural Diversity ◽  
Shannon Index ◽  
Forest Stand ◽  
Simpson Index ◽  
Southern Ontario ◽  
Theoretical Concepts ◽  
Size Diversity

Theoretical concepts pertaining to the marginal cost (MC) of the structural diversity of a forest stand are developed. A matrix growth model is estimated for mixed uneven-aged forest stands of hard maple (Acer saccharum Marsh.) from southern Ontario. The estimated growth model is used to derive the MC equations for the Shannon and the Simpson indices of total structural diversity (TSD), species diversity (SD), and tree-size diversity (TD). The effects of exclusion and inclusion of the opportunity cost (OC) on the MC of the TSD are compared. The contributions of SD and TD to the MC of the TSD are disaggregated. The MCs of TSD, SD, and TD for the Shannon and the Simpson indices are iso-elastic. The elasticity of the MC of the TSD for the inclusion of OC is greater than the elasticity of MC of the TSD for the exclusion of OC. The elasticities of MC of TSD, SD, and TD for the Shannon index are greater than the elasticities of MC of TSD, SD, and TD, respectively, for the Simpson index. The elasticities of MC of SD are smaller than the elasticities of MC of TD, for both indices. However, these results are specific to the hard maple forests of southern Ontario and cannot be generalized. Some general features of MC equations of structural diversity are discussed.

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