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Combinatorial library-based design with Basis Products

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Abstract

Uncovering useful lead compounds from a vast virtual library of synthesizable compounds continues to be of tremendous interest to pharmaceutical researchers. Here we present the concept of Basis Products (BPs), a new and broadly applicable method for achieving efficient selections from a combinatorial library. By definition, Basis Products are a strategically selected subset of compounds from a potentially very large combinatorial library, and any compound in a combinatorial library can represented by its BPs. In this article we will show how to use BP docking scores to find the top compounds of a combinatorial library. Compared with the brute-force docking of an entire virtual library, docking with BPs are much more efficient because of the substantial size reduction, saving both time and resources. We will also demonstrate how BPs can be used for property-based combinatorial library designs. Furthermore, BPs can also be considered as fragments carrying chemistry knowledge, hence they can potentially be used in combination with any fragment-based design method. Therefore, BPs can be used to integrate combinatorial design with structure-based design and/or fragment-based design. Other potential applications of BPs include lead hopping and consensus core building, which we will describe briefly as well in this report.

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Acknowledgments

The authors would like to thank Atsuo Kuki for his visionary guidance of PGVL Hub project at Pfizer, Jerry Hu for his help in generating data for Table 2, and a long list of other colleagues who helped in one way or another. We’d also like to thank Beth Lunney for reading the manuscript and offering insightful feedbacks.

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Author notes

  1. Shenghua Shi & Tom Thacher

    Present address: Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA, 94710, USA

Authors and Affiliations

  1. Department of Computational and Structural Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA, 92121, USA

    Joe Zhongxiang Zhou, Shenghua Shi, Jim Na, Zhengwei Peng & Tom Thacher

  2. Virtual Chemistry Inc., 12110 Salix Way, San Diego, CA, 92129, USA

    Tom Thacher

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  1. Joe Zhongxiang Zhou
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  2. Shenghua Shi
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Correspondence to Joe Zhongxiang Zhou.

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Zhou, J.Z., Shi, S., Na, J. et al. Combinatorial library-based design with Basis Products. J Comput Aided Mol Des 23, 725–736 (2009). https://doi.org/10.1007/s10822-009-9297-9

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  • DOI: https://doi.org/10.1007/s10822-009-9297-9

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