9N48

Crystal structure of PAK1 bound to compound C1

This is a non-PDB format compatible entry.

Summary for 9N48

• Entry DOI: 10.2210/pdb9n48/pdb
• Descriptor: Glutathione S-transferase class-mu 26 kDa isozyme,Serine/threonine-protein kinase PAK 1, (6M)-8-[2-(2-aminoethoxy)ethyl]-6-[2-chloro-3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (3 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 123646.87

Authors

Wang, W.,Oh, A.,Kiefer, J.R.,Hsu, P.L. (deposition date: 2025-02-02, release date: 2025-06-25, Last modification date: 2025-07-02)

Primary citation

Walters, B.T.,Patapoff, A.W.,Kiefer, J.R.,Wu, P.,Wang, W.
Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.
J.Chem.Inf.Model., 65:6144-6154, 2025

PubMed Abstract: We introduce hydrogen-exchange experimental structure prediction (HX-ESP), a method that integrates hydrogen exchange (HX) data with molecular dynamics (MD) simulations to accurately predict ligand binding modes, even for targets requiring significant conformational changes. Benchmarking HX-ESP by fitting two ligands to PAK1 and four ligands to MAP4K1 (HPK1) and comparing the results to X-ray crystallography structures, demonstrates that HX-ESP can identify binding modes across a range of affinities significantly outperforming flexible docking for ligands necessitating large conformational adjustments. By objectively guiding simulations with experimental HX data, HX-ESP overcomes the long time scales required for binding predictions using traditional MD. This advancement enhances the accuracy of computational modeling in drug discovery and thus will accelerate the development of effective therapeutics.

PubMed: 40495786
DOI: 10.1021/acs.jcim.5c00397

Experimental method

X-RAY DIFFRACTION (1.85 Å)