Dataset Information

Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

ABSTRACT: Large purchasable screening libraries of small molecules afforded by commercial vendors are indispensable sources for virtual screening (VS). Selecting an optimal screening library for a specific VS campaign is quite important to improve the success rates and avoid wasting resources in later experimental phases. Analysis of the structural features and molecular diversity for different screening libraries can provide valuable information to the decision making process when selecting screening libraries for VS. In this study, the structural features and scaffold diversity of eleven purchasable screening libraries and Traditional Chinese Medicine Compound Database (TCMCD) were analyzed and compared. Their scaffold diversity represented by the Murcko frameworks and Level 1 scaffolds was characterized by the scaffold counts and cumulative scaffold frequency plots, and visualized by Tree Maps and SAR Maps. The analysis demonstrates that, based on the standardized subsets with similar molecular weight distributions, Chembridge, ChemicalBlock, Mucle, TCMCD and VitasM are more structurally diverse than the others. Compared with all purchasable screening libraries, TCMCD has the highest structural complexity indeed but more conservative molecular scaffolds. Moreover, we found that some representative scaffolds were important components of drug candidates against different drug targets, such as kinases and guanosine-binding protein coupled receptors, and therefore the molecules containing pharmacologically important scaffolds found in screening libraries might be potential inhibitors against the relevant targets. This study may provide valuable perspective on which purchasable compound libraries are better for you to screen. Graphical abstract Selecting diverse compound libraries with scaffold analyses.

SUBMITTER: Shang J

PROVIDER: S-EPMC5400773 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

Shang Jun J Sun Huiyong H Liu Hui H Chen Fu F Tian Sheng S Pan Peichen P Li Dan D Kong Dexin D Hou Tingjun T

Journal of cheminformatics 20170421 1

Large purchasable screening libraries of small molecules afforded by commercial vendors are indispensable sources for virtual screening (VS). Selecting an optimal screening library for a specific VS campaign is quite important to improve the success rates and avoid wasting resources in later experimental phases. Analysis of the structural features and molecular diversity for different screening libraries can provide valuable information to the decision making process when selecting screening lib ...[more]

PMID: 29086044

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Project description:BackgroundThe recent public availability of the human metabolome and natural product datasets has revitalized "metabolite-likeness" and "natural product-likeness" as a drug design concept to design lead libraries targeting specific pathways. Many reports have analyzed the physicochemical property space of biologically important datasets, with only a few comprehensively characterizing the scaffold diversity in public datasets of biological interest. With large collections of high quality public data currently available, we carried out a comparative analysis of current day leads with other biologically relevant datasets.ResultsIn this study, we note a two-fold enrichment of metabolite scaffolds in drug dataset (42%) as compared to currently used lead libraries (23%). We also note that only a small percentage (5%) of natural product scaffolds space is shared by the lead dataset. We have identified specific scaffolds that are present in metabolites and natural products, with close counterparts in the drugs, but are missing in the lead dataset. To determine the distribution of compounds in physicochemical property space we analyzed the molecular polar surface area, the molecular solubility, the number of rings and the number of rotatable bonds in addition to four well-known Lipinski properties. Here, we note that, with only few exceptions, most of the drugs follow Lipinski's rule. The average values of the molecular polar surface area and the molecular solubility in metabolites is the highest while the number of rings is the lowest. In addition, we note that natural products contain the maximum number of rings and the rotatable bonds than any other dataset under consideration.ConclusionsCurrently used lead libraries make little use of the metabolites and natural products scaffold space. We believe that metabolites and natural products are recognized by at least one protein in the biosphere therefore, sampling the fragment and scaffold space of these compounds, along with the knowledge of distribution in physicochemical property space, can result in better lead libraries. Hence, we recommend the greater use of metabolites and natural products while designing lead libraries. Nevertheless, metabolites have a limited distribution in chemical space that limits the usage of metabolites in library design.

Dataset Information

Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

Publications

Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

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