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

Jun Shang,Peichen Pan,Dexin Kong,Hui Liu,Huiyong Sun,Sheng Tian,Fu Chen,Tingjun Hou,Dan Li

doi:10.1186/s13321-017-0212-4

Jun Shang, Peichen Pan + Show 7 more

Open Access

https://doi.org/10.1186/s13321-017-0212-4

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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 abstractSelecting diverse compound libraries with scaffold analyses.

Highlights

Virtual screening (VS) based on a variety of ligand-based or structure-based drug design approaches, such as property-based or drug-likeness rules, quantitative structure– activity relationship (QSAR) models, pharmacophore hypotheses, molecular docking, has become a powerful way to find hits in drug discovery
Traditional Chinese Medicine Compound Database (TCMCD) developed in our group was included in this study, and it contains 57,809 molecules with molecular weight (MW) lower than 800, which are found in more than 5000 herbs used in traditional Chinese medicines (TCM) [17,18,19]
The percentages of molecules that do not have any ring in the standardized subsets were calculated, and they are 0.12, 0.34, 0.51, 0.58, 0.24, 0.56, 0.48, 0.08, 4.71, 0.96, 0.49 and 0.36% for ChemBridge, ChemDiv, ChemicalBlock, Enamine, LifeChemicals, Maybridge, Mcule, Specs, TCMCD, UORSY, VitasM and ZelinskyInstitute, respectively

Summary

Introduction

Virtual screening (VS) based on a variety of ligand-based or structure-based drug design approaches, such as property-based or drug-likeness rules, quantitative structure– activity relationship (QSAR) models, pharmacophore hypotheses, molecular docking, has become a powerful way to find hits in drug discovery. The chemical space of a compound library should be examined by molecular structures, especially chemical scaffolds, which has a huge impact on the success rate in biological screenings [4]. Markush structures are usually used in patent applications to define chemical series [6], but they may be too generic to highlight the important structural features essential for pharmaceutical activity. Another scaffold representation is the Murcko framework proposed by Bemis and Murcko [7]. Analysis of compound libraries by using the RECAP representation may be a good way to explore the synthetic feasibility of a molecule

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