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Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

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Abstract

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

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Authors and Affiliations

  1. Karyopharm Therapeutics, 2 Mercer Road, Natick, MA, 01760, USA

    Ori Kalid, Sharon Shechter & Sharon Shacham

  2. Ori Kalid Consulting, Habotnim 40, 37013, Pardes-Hanna, Israel

    Ori Kalid

  3. Schrödinger Inc., 120 West 45th Street, New York, NY, 10036, USA

    Dora Toledo Warshaviak & Woody Sherman

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  1. Ori Kalid
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Ori Kalid, Dora Toledo Warshaviak: equal contributors.

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Kalid, O., Toledo Warshaviak, D., Shechter, S. et al. Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. J Comput Aided Mol Des 26, 1217–1228 (2012). https://doi.org/10.1007/s10822-012-9611-9

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