Increased Diversity of <i>Libraries from Libraries</i>: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

López‐Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R.; Nabney, Ian T.; Houghten, Richard A.; Medina‐Franco, José L.

doi:10.1111/j.1747-0285.2011.01100.x

Cited by 30 publications

(22 citation statements)

References 43 publications

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“…The similarity values were calculated from a random sample of 1000 molecules each except natural products from Specs and the TPIMS set where all molecules were used. It has been shown that random samples of 1000 molecules are representative of the molecular diversity within a larger collection (30)(31)(32). Results of three random samples are presented in Table S1 of the Supporting Information.…”

Section: Compound Databasesmentioning

confidence: 99%

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

2012

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Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in-house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery.Key words: chemoinformatics, cyclic system, molecular diversity, natural product, Shannon entropy, Traditional Chinese Medicine.Abbreviations: CSR, cumulative scaffold recovery; MACCS, Molecular ACCess System; MEQI, Molecular Equivalence Index; MOE, molecular operating environment; SE, Shannon entropy; TCM, Traditional Chinese Medicine.Received 22 June 2012, revised 18 July 2012 and accepted for publication 19 July 2012Traditionally, natural products have played a major role in drug discovery and development by providing novel chemical scaffolds, and serving as leads or drugs (1,2). For many years, 80% of drugs were either natural products or natural product-derived compounds. Even in the modern era, after the advent of techniques such as high-throughput screening of synthetic libraries, half of the drugs approved since 1994 are based on natural products research (3,4). Recent comprehensive reviews of natural products, or compounds inspired by natural products, indicate that more than 100 natural product compounds are currently in clinical trials. Natural products offer the advantage of discovering novel structural classes (5,6) because of their well-documented better coverage of chemical space relative to large synthetic compounds (7). Hence, the structural or chemical diversity of natural products can be utilized to access bioactive compounds with novel scaffolds (7-9). The inclusion of sources of natural products in drug discovery would open up more avenues for new classes of drugs (10) as well as new chemical entities, evidenced by studies that show structural or chemical complementarity between natural...

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Section: Compound Databasesmentioning

confidence: 99%

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

2012

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“…(3). Combinatorial libraries assembled in libraries from libraries [82] have also been virtually screened using docking with a homology model of the catalytic domain of DNMT1 [76].…”

Section: Virtual Screeningmentioning

confidence: 99%

Inhibitors of DNA Methyltransferases: Insights from Computational Studies

Yoo¹,

Medina-Franco²

2012

CMC

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DNA methyltransferases (DNMTs) are a family of epigenetic enzymes for which inhibition is an attractive strategy for the treatment of cancer and other diseases. In synergy with experimental approaches, computational methods are increasingly being used to identify and optimize the activity of inhibitors of DNMTs as well as to rationalize at the molecular level of the mechanism of established inhibitors. Recently, a crystallographic structure of the methyltransferase domain of human DNMT1 bound to unmethylated DNA was published encouraging the application of structure-based approaches to design and optimize the activity of currently known inhibitors. Herein, we review the progress in the discovery and optimization of inhibitors of DNMTs using computational approaches including homology modeling, docking, pharmacophore modeling, molecular dynamics, and virtual screening.

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“…The six descriptors used here have been used widely to compare the property space of compound collections [12,13,26].…”

Section: Physicochemical Propertiesmentioning

confidence: 99%

“…There are available several chemoinformatic tools that have been employed by the authors and other research groups to analyze chemical libraries. Representative and recent examples include the characterization of the NCI database [12], a natural product collection available in ZINC [12] and other natural products databases [14,15], several commercially available libraries and approved drugs [16,17] and public repositories [18].…”

Section: Introductionmentioning

confidence: 99%

Chemoinformatic Approaches for Inhibitors of DNA Methyltransferases: Comprehensive Characterization of Screening Libraries

Yoo¹,

Luis²

2011

CMB

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Virtual screening of compound databases is a promising approach to identify inhibitors of DNA methyltransferases and other epigenetic targets. An important first step before conducting virtual screening is to characterize the structural diversity and chemical space coverage of the screening collections. Herein, we report a comprehensive chemoinformatic characterization of novel screening libraries, including a focused collection directed to inhibitors of DNA methyltransferases (DNMTs), and two natural product databases. The compound databases were assessed in terms of physicochemical properties, molecular scaffolds, and fingerprints. As part of the scaffold diversity analysis, a recently developed method, based on Shannon Entropy, was used. The overall approach enabled the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity. Overall, the analysis of the distribution of physicochemical properties indicates that the DNMT focused library and the two natural products collections have molecules with properties similar to approved drugs. Moreover, the natural products databases analyzed in this work have different chemical structures from approved drugs and synthetic databases and therefore are attractive for virtual screening for DNMT inhibitors. The scaffold analysis revealed that the focused library has, overall, the largest scaffold diversity and that the most frequent scaffolds are not identified in the other analyzed collections. Therefore, the focused library is also attractive to perform virtual and experimental screening for novel inhibitors. This study represents a first step towards the virtual screening of novel compound databases to identify inhibitors of DNMTs. Results of this study are general and can be used for the virtual screening of the compound databases against targets directed to other therapeutic applications.

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Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis‐Diazacyclic Libraries

Cited by 30 publications

References 43 publications

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

Inhibitors of DNA Methyltransferases: Insights from Computational Studies

Chemoinformatic Approaches for Inhibitors of DNA Methyltransferases: Comprehensive Characterization of Screening Libraries

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