Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding.

By E. B. Miller, Robert B. Murphy, Daniel J. Sindhikara, K. Borrelli, Matthew J. Grisewood, Fabio Ranalli, Steve Dixon, Steven V Jerome, Nicholas A Boyles, T. Day and 6 more. 2021

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We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 Å in over 90% of cross-docking cases. We further demonstrate these predicted ligand-receptor structures were sufficiently accurate to prospectively enable predictive structure-based drug discovery for challenging targets, substantially expanding the domain of applicability for such methods.

Subfields: Computational Theory and Mathematics, Organic Chemistry, Radiology, Nuclear Medicine and Imaging, Computational Biology & Bioinformatics, Computational Chemistry & Drug Discovery