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Avalanche for shape and feature-based virtual screening with 3D alignment

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Abstract

This report introduces a new ligand-based virtual screening tool called Avalanche that incorporates both shape- and feature-based comparison with three-dimensional (3D) alignment between the query molecule and test compounds residing in a chemical database. Avalanche proceeds in two steps. The first step is an extremely rapid shape/feature based comparison which is used to narrow the focus from potentially millions or billions of candidate molecules and conformations to a more manageable number that are then passed to the second step. The second step is a detailed yet still rapid 3D alignment of the remaining candidate conformations to the query conformation. Using the 3D alignment, these remaining candidate conformations are scored, re-ranked and presented to the user as the top hits for further visualization and evaluation. To provide further insight into the method, the results from two prospective virtual screens are presented which show the ability of Avalanche to identify hits from chemical databases that would likely be missed by common substructure-based or fingerprint-based search methods. The Avalanche method is extended to enable patent landscaping, i.e., structural refinements to improve the patentability of hits for deployment in drug discovery campaigns.

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Author notes

  1. David J. Diller

    Present address: CMD Bioscience, 5 Science Park, New Haven, CT, 06511, USA

Authors and Affiliations

  1. Snowdon, Inc., Princeton, NJ, 08540, USA

    David J. Diller

  2. Department of Medicine, New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA

    Nancy D. Connell

  3. Department of Pharmacology, Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ, 08854, USA

    William J. Welsh

Authors
  1. David J. Diller
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  2. Nancy D. Connell
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  3. William J. Welsh
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Corresponding authors

Correspondence to David J. Diller or William J. Welsh.

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Diller, D.J., Connell, N.D. & Welsh, W.J. Avalanche for shape and feature-based virtual screening with 3D alignment. J Comput Aided Mol Des 29, 1015–1024 (2015). https://doi.org/10.1007/s10822-015-9875-y

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  • DOI: https://doi.org/10.1007/s10822-015-9875-y

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