Using Ligand‐Mapping Simulations to Design a Ligand Selectively Targeting a Cryptic Surface Pocket of Polo‐Like Kinase 1

Abstract

Ein Verfahren mit expliziter Ligandenkartierung war geeignet, um eine unerkannt gebliebene hydrophobe Tasche in der Polo‐like Kinase 1 (Plk1) zu entdecken. Ein neuartiger Ligandenbindungsmodus konnte vorhergesagt und für den Entwurf eines neuen Liganden mit hoher Affinität für Plk1 genutzt werden. Eine Röntgenstrukturanalyse bestätigt eine spezifische Bindung des Liganden in der vorgesehenen Tasche.

Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

“…Accordingly, the inherent flexibility, amphiphilicity of small glycols would enable an interplay between the dynamics of the flexible, less hydrophobic cryptic binding site and the dynamics of the glycol molecule interacting with the site. It has been shown, through use of various force-field in MD simulations of different protein systems with known cryptic sites, that cryptic pockets are unstable without ligands and prefer to stay in closed state in their absence [4, 21]. We also observed closure of the cryptic pocket in RBSX-W6A structure (PDB code 5XC0, Table 1) (Fig.…”

“…The cryptic site of RBSX-W6A showed properties similar to the properties of cryptic sites characterized in other protein systems [6], and interacted with glycols through hydrogen bond and van der Waals contacts. Explicit-solvent MD simulations of RBSX-W6A with exposed-state of the cryptic site revealed closure of the site in absence of glycol molecule whereas no change in the cryptic site was observed in MD simulations of RBSX-W6A with occluded-state of the cryptic site, showing that cryptic sites are unstable without ligands and prefer to stay in closed state in their absence [4, 21]. The combined crystal structure and simulation results thus justifies the role of glycols in identifying the cryptic site of RBSX-W6A.…”

Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design

“…The use of hydrophobic probes is of particular interest because it reduces the solvent polarity, thus facilitating the opening and enlargement of hydrophobic pockets that may otherwise remain undetected in pure water simulations of the protein. 7 Ligand-mapping MD (LMMD) 13 , 14 is one of two probe-based MD simulation methods that employ hydrophobic probes for pocket detection. In contrast to the related site identification by ligand competitive saturation (SILCS) method, 9 LMMD does not require the addition of artificial interligand repulsive energy terms because of the use of relatively low concentrations of hydrophobic probes to avoid ligand aggregation.…”

“…LMMD simulations have been shown to be especially useful at revealing cryptic binding sites 14 and were previously used to guide the design of a ligand to target a cryptic pocket. 13 Recently, LMMD has also been established as a reliable method for the identification of hydrophobic peptide binding sites. 15 To date, probe-based MD simulations have mostly been limited to the reproduction of known structural data.…”

Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors

“…Overall, the preceding analysis reveals that the formation of the secondary pocket cannot be simply ascribed to the conformational change of a specific residue, as has been described in other cases. For instance, the accessibility to cryptic pockets at the protein-binding interface of eIF4E depends on the gating movement of Trp73 [ 57 ], or the disclosure of a hydrophobic pocket by side-chain movements of Tyr417 and Tyr481 in polo-like kinase 1 [ 58 ]. Rather, the collective motions of loops 8–14, 154–169, and 307–318 determine the structural features of the cryptic pocket found in BACE-1, which exhibits a large variation in the overall shape and size (Figs 5 and 6 ).…”