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000862493 1001_ $$0P:(DE-HGF)0$$aSchmidt, Denis$$b0
000862493 245__ $$aCosolvent-enhanced Sampling and Unbiased Identification of Cryptic Pockets Suitable for Structure-based Drug Design
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000862493 520__ $$aModulating protein activity with small molecules binding to cryptic pockets offers great opportunities to overcome hurdles in drug design. Cryptic sites are atypical binding sites in proteins that are closed in the absence of a stabilizing ligand and are thus inherently difficult to identify. Many studies have proposed methods to predict cryptic sites. However, a general approach to prospectively sample open conformations of these sites and to identify cryptic pockets in an unbiased manner suitable for structure-based drug design remains elusive. Here, we describe an all-atom, explicit cosolvent, molecular dynamics (MD) simulations-based workflow to sample the open states of cryptic sites and identify opened pockets, in a manner that does not require a priori knowledge about these sites. Furthermore, the workflow relies on a target-independent parameterization that only distinguishes between binding pockets for peptides or small-molecules. We validated our approach on a diverse test set of seven proteins with crystallographically determined cryptic sites. The known cryptic sites were found among the three highest-ranked predicted cryptic sites, and an open site conformation was sampled and selected for most of the systems. Crystallographic ligand poses were well reproduced by docking into these identified open conformations for five of the systems. When the fully open state could not be reproduced, we were still able to predict the location of the cryptic site, or identify other cryptic sites that could be retrospectively validated with knowledge of the protein target. These characteristics render our approach valuable for investigating novel protein targets without any prior information.
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000862493 7001_ $$0P:(DE-HGF)0$$aBoehm, Markus$$b1
000862493 7001_ $$0P:(DE-HGF)0$$aMcClendon, Christopher L.$$b2
000862493 7001_ $$0P:(DE-HGF)0$$aTorella, Rubben$$b3
000862493 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b4$$eCorresponding author$$ufzj
000862493 773__ $$0PERI:(DE-600)2166976-4$$a10.1021/acs.jctc.8b01295$$gp. acs.jctc.8b01295$$n5$$p3331–3343$$tJournal of chemical theory and computation$$v15$$x1549-9626$$y2019
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000862493 8564_ $$uhttps://juser.fz-juelich.de/record/862493/files/sampling_transient_pockets_Rev_final.pdf$$yPublished on 2019-04-18. Available in OpenAccess from 2020-04-18.
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