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An integrated suite of modeling tools that empower scientists in structure- and property-based drug design

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Abstract

Structure- and property-based drug design is an integral part of modern drug discovery, enabling the design of compounds aimed at improving potency and selectivity. However, building molecules using desktop modeling tools can easily lead to poor designs that appear to form many favorable interactions with the protein’s active site. Although a proposed molecule looks good on screen and appears to fit into the protein site X-ray crystal structure or pharmacophore model, doing so might require a high-energy small molecule conformation, which would likely be inactive. To help scientists make better design decisions, we have built integrated, easy-to-use, interactive software tools to perform docking experiments, de novo design, shape and pharmacophore based database searches, small molecule conformational analysis and molecular property calculations. Using a combination of these tools helps scientists in assessing the likelihood that a designed molecule will be active and have desirable drug metabolism and pharmacokinetic properties. Small molecule discovery success requires project teams to rapidly design and synthesize potent molecules with good ADME properties. Empowering scientists to evaluate ideas quickly and make better design decisions with easy-to-access and easy-to-understand software on their desktop is now a key part of our discovery process.

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Acknowledgments

We thank the late Dr. Warren DeLano for help with creating custom menus in PyMOL, and for implementing a webserver in PyMOL that enabled integration with external programs. We also thank Dr. Matthias Keil, Dr. Howard Feldman and their Chemical Computing Group colleagues for implementing features in MOE to enable integration with external software tools. Lastly, we thank Genentech colleagues for providing useful feedback.

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Authors and Affiliations

  1. Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Jianwen A. Feng, Ignacio Aliagas, Philippe Bergeron, Jeff M. Blaney, Michael F. T. Koehler, Man-Ling Lee, Daniel F. Ortwine, Vickie Tsui & Alberto Gobbi

  2. Bioinformatics and Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Johnny Wu

  3. Corvus Pharmaceuticals, Inc, Burlingame, CA, 94010, USA

    Erin K. Bradley

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  1. Jianwen A. Feng
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  2. Ignacio Aliagas
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  3. Philippe Bergeron
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Correspondence to Jianwen A. Feng.

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Feng, J.A., Aliagas, I., Bergeron, P. et al. An integrated suite of modeling tools that empower scientists in structure- and property-based drug design. J Comput Aided Mol Des 29, 511–523 (2015). https://doi.org/10.1007/s10822-015-9845-4

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