Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors

Abstract

P21-activated kinases (PAKs) are serine/threonine protein kinases that are subdivided into two groups on the basis of their domain architecture: group-I (PAK1–3) and group-II (PAK4–6). PAKs are considered as attractive drug targets that play vital role in cell proliferation, survival, motility, angiogenesis and cytoskeletal dynamics. In current study, molecular dynamics simulation-based comparative residual contributions and differential transitions were monitored in both active and inactive states of human PAK homologs for therapeutic intervention. Due to their involvement in cancer, infectious diseases, and neurological disorders, it is inevitable to develop novel therapeutic strategies that specifically target PAKs on the basis of their activity pattern. In order to isolate novel inhibitors that are able to bind at the active sites of PAK1 and PAK4, high throughput structure-based virtual screening was performed. Multiple lead compounds were proposed on the basis of their binding potential and targeting region either phosphorylated (active) or unphosphorylated PAK isoform (inactive). Thus, ATP-competitive inhibitors may prove ideal therapeutic choice against PAK family members. The detailed conformational readjustements occurring in the PAKs upon phosphorylation-dephosphorylation events may serve as starting point for devising novel drug molecules that are able to target on activity basis. Overall, the observations of current study may add valuable contribution in the inventory of novel inhibitors that may serve as attractive lead compounds for targeting PAK family members on the basis of activity-based conformational changes.

The Inhibitory Mechanism of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as Inhibitors of P21-Activated Kinase 4 through Molecular Dynamics Simulation

“…PAK4 has the common structure of protein kinases, containing an N-terminal regulatory domain and a C-terminal kinase domain [ 12 ]. The C-terminal kinase domain of PAK4 catalyzes γ-phosphate transfer from ATP to the receptor polypeptide [ 12 ]. Its kinase domain is shown in Figure 1 , with residues ranging from Ser300 to Arg591 [ 13 ].…”

“…Its kinase domain is shown in Figure 1 , with residues ranging from Ser300 to Arg591 [ 13 ]. It contains two kinase lobes [ 14 ], the N-lobe consisting mainly of five antiparallel aligned β-sheets (β1-β5) and three α-helices (αA-αC), and the C-lobe consisting mainly of α-helices (αD-αJ) [ 12 , 15 ]. The two kinase lobes are connected by a hinge, and a larger cleft between the two lobes is used to bind the phosphate donor ATP [ 14 ].…”

SHP-1 tyrosine phosphatase binding to c-Src kinase phosphor-dependent conformations: A comparative structural framework

“…Protein tyrosine phosphorylation is a post-translational modification that plays an essential role in cell growth, proliferation, and differentiation [1,2]. Tyrosine phosphorylation is a fundamental mechanism in the eukaryotic cellular signaling pathways [3].…”

WaterMap and Molecular Dynamic Simulation-Guided Discovery of Potential PAK1 Inhibitors Using Repurposing Approaches

“…However, designing a highly selective PAK1 inhibitor is quite challenging because of a high homology of the kinase domain and is further hampered by high toxicity, poor potency, poor solubility, isoform specificity, and inadequate testing of existing inhibitors. − Considering these issues, in this work, a synergistic computational approach was used to repurpose FDA-approved drugs from the DrugBank database against PAK1. − This synergistic approach includes molecular docking using Glide to understand the binding mode and affinity of the drug molecules revealed through potential noncovalent interaction energies. , However, the current scoring functions neglect the contributions of protein flexibility and the effects of explicit water molecules at the binding site, which could provide a better estimation of the complex’s binding affinity. − …”