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Hit diffusion: limitations to drug discovery and structure-based design

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For the special issue in honor of Gerry Maggiora

...and the first one now

will later be last…

—Bob Dylan “The Times They Are A-Changin”.

Abstract

Modern drug discovery employs a ‘screening funnel’ to pick compounds worthy of advancing to the clinic, a multi-step process linking a series of assays. Molecules which are active in in vitro assays are passed to a cell-based assay, etc. Each pair of assays may be discordant, due to their measuring similar but not identical properties. This can create an enormous potential to overlook the best molecules, which we highlight here through an understanding of relationships we call ‘hit diffusion’. Understanding hit diffusion has important implications for structure-based design, and drug discovery overall. The biophysical bases for assay discordance are outlined, and some strategies for ameliorating the hit diffusion problem are described.

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Acknowledgements

The origin of these thoughts was a recent, informal conversation with M. Mense, at the Cystic Fibrosis Foundation. Conversations over many years with V. Groppi, M. Lajiness and G. Maggiora (then at Upjohn/Pharmacia & Upjohn/Pharmacia), and R. Guha (now at Vertex) were also very helpful.

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  1. Van Drie Research LLC, North Andover, MA, USA

    John H. Van Drie

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  1. John H. Van Drie
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Correspondence to John H. Van Drie.

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Van Drie, J.H. Hit diffusion: limitations to drug discovery and structure-based design. J Comput Aided Mol Des 36, 373–379 (2022). https://doi.org/10.1007/s10822-021-00425-2

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  • DOI: https://doi.org/10.1007/s10822-021-00425-2

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