ct1c01177_si_001.pdf (2.48 MB)
Accelerated Ligand-Mapping Molecular Dynamics Simulations for the Detection of Recalcitrant Cryptic Pockets and Occluded Binding Sites
journal contribution
posted on 2022-02-17, 20:09 authored by Justin Tze-Yang Ng, Yaw Sing TanThe
identification and characterization of binding sites is a critical
component of structure-based drug design (SBDD). Probe-based/cosolvent
molecular dynamics (MD) methods that allow for protein flexibility
have been developed to predict ligand binding sites. However, cryptic
pockets that appear only upon ligand binding and occluded binding
sites with no access to the solvent pose significant challenges to
these methods. Here, we report the development of accelerated ligand-mapping
MD (aLMMD), which combines accelerated MD with LMMD, for the detection
of these challenging binding sites. The method was validated on five
proteins with what we term “recalcitrant” cryptic pockets,
which are deeply buried pockets that require extensive movement of
the protein backbone to expose, and three proteins with occluded binding
sites. In all the cases, aLMMD was able to detect and sample the binding
sites. Our results suggest that aLMMD could be used as a general approach
for the detection of such elusive binding sites in protein targets,
thus providing valuable information for SBDD.
History
Usage metrics
Categories
Keywords
require extensive movementcosolvent molecular dynamicsdeeply buried pocketsoccluded binding siteselusive binding siteschallenging binding sitesupon ligand bindingrecalcitrant cryptic pocketsbased drug designcombines accelerated mdbinding sitescryptic pocketsaccelerated ligandthree proteinsresults suggestprotein targetsprotein flexibilityprotein backbonemapping mdgeneral approachfive proteinscritical component