Computational Insight into p21‐Activated Kinase 4 Inhibition: A Combined Ligand‐ and Structure‐Based Approach

Abstract

p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases including cancer. Targeting this kinase with specific inhibitors is of great interest in the treatment of cancer. In this study, PAK4 and its interaction with ATP-competitive inhibitors was investigated by a combined ligand- and structure-based approach. First, a ligand-based pharmacophore model was generated, consisting of five chemical features: a positive ionizable center, two hydrophobic groups, a hydrogen bond donor, and a hydrogen bond acceptor, which is consistent with available SAR information. The characteristics of the active site were then described as a topological region and used in docking of nine selected inhibitors. Combination of the pharmacophore model and results from the docking studies allowed us to weigh the various pharmacophore features and to identify the positive ionizable center as a spacer rather than an essential point. This research led to the proposal of an interaction model inside the PAK4 active site and provided guidance for the design of more potent PAK4 inhibitors.

Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

“…However, a severe problem was the docking accuracy of cocrystallized complexes which docked new ligands rather than self-docking [ 24 , 25 ]. The great approach to test this was cross-docking; for the same target, there is usually more than one ligand-receptor complex; what we do is dock one's ligand into other complexes.…”

“…Crystal structures of PTP1B (PDB code: 2CM7, 2CMA, 2CMB, 2CNG, 2QBP, 2QBQ, and 2ZN7) were imported into Glide 9.7, defined as the receptor structure and the location of active site with a box of size 13 Å × 13 Å × 13 Å. The OPLS_2005 force field was used for grid generation [ 24 , 25 ]. The standard precision (SP) and the extra precision (XP) protocols were set for docking studies with two crucial residues, Lys120 and Arg221, in constrained binding to get accurate results.…”

Structure-based virtual screening and ADME/T-based prediction analysis for the discovery of novel antifungal CYP51 inhibitors

“…The compounds with appropriate binding energy values (≤6) were selected. 19,20 Finally, sixteen compounds were chosen and purchased for in vitro bioassay testing (Table 1).…”

Structure-based virtual screening and ADME/T-based profiling for low molecular weight chemical starting points as p21-activated kinase 4 inhibitors

“…The two pharmacophore models were previously constructed by clustering common chemical features from docked poses of nine PAK4 inhibitors and were validated as ideal pharmacophore models that not only properly reect the structural information inside the binding site of PAK4, but also contain chemical features from more active compounds. 10 To further analyze the pharmacophore features, the two pharmacophore models herein were superimposed on the PAK4 binding site. The high resolution crystal structure of PAK4 with potent ligand (PF-3758309) (PDB code: 2X4Z) was chosen for modeling, and signicant result of the cross-docking simulation part previously reported.…”

“…The high resolution crystal structure of PAK4 with potent ligand (PF-3758309) (PDB code: 2X4Z) was chosen for modeling, and signicant result of the cross-docking simulation part previously reported. 10 As shown in Fig. 1A, PF-3758309 forms three contacts with the hinger region through H-bond interactions with the pyrrolopyrazole core and the amine of the thienopyrimidine ring; the dimethylamine group forms charge-charge interaction with Asp458; three hydrophobic interactions between PF-3758309 and the PAK4 protein are observed, including (i) thiophene and Gly401 located in pocket A, (ii) gem-dimethyl group of the pyrrolopyrazole core and Met395 contained in pocket C, and (iii) benzyl moiety and G-loop.…”