Cheminformatics approaches to analyze diversity in compound screening libraries

Akella, Lakshmi B.; DeCaprio, David

doi:10.1016/j.cbpa.2010.03.017

Cited by 85 publications

(59 citation statements)

References 43 publications

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“…Indeed, our current discovery collection at the Broad Institute reflects many considerations (26,(63)(64)(65)(66)(67) that were never applied to the compounds in this study. Rather, we aim to promote a way of thinking about compound sets that is unbiased, quantitative, and decision-oriented, not to prescribe which particular decisions should be made.…”

Section: Discussionmentioning

confidence: 99%

“…Significant progress has been made quantifying and visualizing properties of compound sets (26), including methods that relate structure to intuitive notions of shape (27)(28)(29), and similarity fusion methods (30)(31)(32)(33) that describe relationships between sets. Moreover, chemical similarity and diversity analyses continue to progress (34)(35)(36)(37), including studies using Shannon entropy (38) as a measure of structure information among compounds (39)(40)(41), addressing reagent selection (42), database similarity searches (43), and scaffold diversity (44).…”

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confidence: 99%

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Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Clemons

Wilson

Dančík

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Using a diverse collection of small molecules we recently found that compound sets from different sources (commercial; academic; natural) have different protein-binding behaviors, and these behaviors correlate with trends in stereochemical complexity for these compound sets. These results lend insight into structural features that synthetic chemists might target when synthesizing screening collections for biological discovery. We report extensive characterization of structural properties and diversity of biological performance for these compounds and expand comparative analyses to include physicochemical properties and three-dimensional shapes of predicted conformers. The results highlight additional similarities and differences between the sets, but also the dependence of such comparisons on the choice of molecular descriptors. Using a protein-binding dataset, we introduce an information-theoretic measure to assess diversity of performance with a constraint on specificity. Rather than relying on finding individual active compounds, this measure allows rational judgment of compound subsets as groups. We also apply this measure to publicly available data from ChemBank for the same compound sets across a diverse group of functional assays. We find that performance diversity of compound sets is relatively stable across a range of property values as judged by this measure, both in protein-binding studies and functional assays. Because building screening collections with improved performance depends on efficient use of synthetic organic chemistry resources, these studies illustrate an important quantitative framework to help prioritize choices made in building such collections.A central theme in applying cheminformatics to discovery chemistry is to relate synthetic decisions to consequences on both chemical structure and biological assay performance. Historically, such efforts focused on small sets of similar compounds, and single performance measurements (1-3), providing guidance to chemists in compound optimization against singletarget proteins or processes (4). However, additional methods are needed to judge large sets of compounds, such as those used in small-molecule screening. Progress toward more valuable screening collections (5) requires unbiased methods to evaluate diversity of assay performance for compound sets rather than performance of individual members.A widely used method to judge compounds for drug discovery is the "rule of 5" (RO5) (6), which predicts poor absorption or permeation for compounds that deviate from property-value constraints: H-bond donors (Hd) and acceptors (Ha), molecular weight (MW), and calculated partition coefficients (cLogP). Recent studies have attempted to refine such rules (7-9) and extend them to other goals (10-13), such as making leads or probes. Such property filters have been debated and reviewed (14-16), and their long-term impact on pharmaceutical research is starting to be analyzed (17, 18). Importantly, exceptions to these rules, including natural products (19-21), ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Clemons

Wilson

Dančík

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Estimating the diversity of a compound collection in the perspective of its potential value for bioactivity is a difficult problem to which various solutions have been proposed [16,35,36], in particular extended-connectivity fingerprints (ECFP) [37]. The MQN-system offers an attractive alternative to appreciate structural diversity, even if quite simple in comparison of the existing methods.…”

Section: Mqn-distance Histograms As Diversity Measurementioning

confidence: 99%

“…Among the various approaches reported sofar to represent chemical space [14][15][16], MQN-space has the advantage of simplicity. For instance chemical spaces have been constructed by assigning dimensions to descriptors such as eigenvalues of matrices constructed from primary descriptors [13,17,18], or more directly to descriptors of molecular structure and calculated physicochemical properties [19,20], or by using various types of fingerprints [21].…”

Section: Introductionmentioning

confidence: 99%

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

Deursen

Blum

Reymond

2011

J Comput Aided Mol Des

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The 4.5 million organic molecules with up to 20 non-hydrogen atoms in PubChem were analyzed using the MQN-system, which consists in 42 integer value descriptors of molecular structure. The 42-dimensional MQN-space was visualised by principal component analysis and representation of the (PC1, PC2), (PC1, PC3) and (PC2, PC3) planes. The molecules were organized according to ring count (PC1, 38% of variance), the molecular size (PC2, 25% of variance), and the H-bond acceptor count (PC3, 12% of variance). Compounds following Lipinski's bioavailability, Oprea's lead-likeness and Congreve's fragment-likeness criteria formed separated groups in MQN-space visible in the (PC2, PC3) plane. MQN-similarity searches of the 4.5 million molecules (see the browser available at www.gdb.unibe.ch) gave significant enrichment factors for recovering groups of fragment-sized bioactive compounds related to ten different biological targets taken from Chembl, allowing leadhopping relationships not seen with substructure fingerprint similarity searches. The diversity of different compound series was analyzed by MQN-distance histograms.

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“…Finally, all library members were cleaved from the solid support using HF·pyridine (pyridine, THF, 50°C) and purified by preparative reverse-phase HPLC to afford the final library of 190 alkaloid/terpenoid-like compounds (both enantiomeric series), comprised of 18 cyclopentapyrrolidinones (11-13), 30 exo-pyrrolines (14-19), 6 cyclooctapyrrolidines (20), 18 vinylpyrrolines (21-23), 6 benzodipyrrolidines (24), and 6 isoindoline dicarboxylates (25) derived from the enyne substrates and 28 isoindoline alcohols (30-38), 24 pyrrolopyridones (36-41), 18 pyrrolopyridine carboxylates (42)(43)(44), and 36 cycloheptapyrrolidine amides (45-50) derived from the diyne substrates. The products were isolated in 20.2% average yield over 5-8 solid-phase steps, at 74.0% average yield per step (SI Appendix, Table S1).…”

Section: Resultsmentioning

confidence: 99%

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

Moura‐Letts¹,

DiBlasi²,

Bauer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Alkaloid and terpenoid natural products display an extensive array of chemical frameworks and biological activities. However such scaffolds remain underrepresented in current screening collections and are, thus, attractive targets for the synthesis of natural product-based libraries that access underexploited regions of chemical space. Recently, we reported a systematic approach to the stereoselective synthesis of multiple alkaloid/terpenoid-like scaffolds using transition metal-mediated cycloaddition and cyclization reactions of enyne and diyne substrates assembled on a tert-butylsulfinamide lynchpin. We report herein the synthesis of a 190-membered library of alkaloid/terpenoid-like molecules using this synthetic approach. Translation to solid-phase synthesis was facilitated by the use of a tert-butyldiarylsilyl (TBDAS) linker that closely mimics the tert-butyldiphenysilyl protecting group used in the original solution-phase route development work. Unexpected differences in stereoselectivity and regioselectivity were observed in some reactions when carried out on solid support. Further, the sulfinamide moiety could be hydrolyzed or oxidized efficiently without compromising the TBDAS linker to provide additional amine and sulfonamide functionalities. Principal component analysis of the structural and physicochemical properties of these molecules confirmed that they access regions of chemical space that overlap with bona fide natural products and are distinct from areas addressed by conventional synthetic drugs and drug-like molecules. The influences of scaffolds and substituents were also evaluated, with both found to have significant impacts on location in chemical space and three-dimensional shape. Broad biological evaluation of this library will provide valuable insights into the abilities of natural product-based libraries to access similarly underexploited regions of biological space. diversity-oriented synthesis | multiscaffold library | asymmetric synthesis | cheminformatics A major goal in the field of diversity-oriented synthesis is the efficient production of small-molecule libraries that address underexploited regions of biologically relevant chemical space to enable the discovery of new biological probes and potential therapeutic lead compounds (1). A key approach to addressing this challenge is to emulate natural products and other biogenetic molecules, which have coevolved with macromolecular biological targets (2). Toward this end, a variety of natural product-based libraries have been synthesized, with promising early results (3). These libraries can be validated initially by evaluation of their structural and physicochemical properties using principal component analysis (PCA) to determine the regions of chemical space that are accessed. Subsequently, screening across a wide range of biological assays provides direct biological validation of the functional capabilities of these libraries.Alkaloids and terpenoids have long served as important small-molecule drugs and leads for drug discovery (4, ...

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Cheminformatics approaches to analyze diversity in compound screening libraries

Cited by 85 publications

References 43 publications

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

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