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Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery

  • Xin Cindy Yan*
    Xin Cindy Yan
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
    *Phone: 617-992-3109. Email: [email protected]
  • John M. Sanders
    John M. Sanders
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Ying-Duo Gao
    Ying-Duo Gao
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
    More by Ying-Duo Gao
  • Matthew Tudor
    Matthew Tudor
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Andrew M. Haidle
    Andrew M. Haidle
    Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Daniel J. Klein
    Daniel J. Klein
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Antonella Converso
    Antonella Converso
    Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Charles A. Lesburg
    Charles A. Lesburg
    Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
  • Yi Zang
    Yi Zang
    Regulatory Affairs, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
    More by Yi Zang
  • , and 
  • Harold B. Wood
    Harold B. Wood
    Chemistry Capabilities for Accelerating Therapeutics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Cite this: J. Chem. Inf. Model. 2020, 60, 9, 4144–4152
Publication Date (Web):April 20, 2020
https://doi.org/10.1021/acs.jcim.0c00113
Copyright © 2020 American Chemical Society

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    Abstract

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    Two orthogonal approaches for hit identification in drug discovery are large-scale in vitro and in silico screening. In recent years, due to the emergence of new targets and a rapid increase in the size of the readily synthesizable chemical space, there is a growing emphasis on the integration of the two techniques to improve the hit finding efficiency. Here, we highlight three examples of drug discovery projects at Merck & Co., Inc., Kenilworth, NJ, USA in which different virtual screening (VS) techniques, each specifically tailored to leverage knowledge available for the target, were utilized to augment the selection of high-quality chemical matter for in vitro assays and to enhance the diversity and tractability of hits. Central to success is a fully integrated workflow combining in silico and experimental expertise at every stage of the hit identification process. We advocate that workflows encompassing VS as part of an integrated hit finding plan should be widely adopted to accelerate hit identification and foster cross-functional collaborations in modern drug discovery.

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    The atomic coordinates and structure factors for HIV integrase crystal structure with compound 3 and FXIa crystal structures with compounds 7 and 11 have been deposited with the Protein Data Bank under the accession codes 6VLM, 6VLU, and 6VLV, respectively. (The authors will release the atomic coordinates and experimental data upon article publication.)

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