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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.

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Tribbles pseudokinases, Tribbles homolog 1 (TRIB1), Tribbles homolog 2 (TRIB2), and Tribbles homolog 3 (TRIB3), bind to constitutive photomorphogenesis protein 1 (COP1) E3 ligase to mediate the regulation of β-catenin expression. The interaction mechanism between COP1 E3 ligase and β-catenin has not been addressed to date.Based on the functional presence of TRIBs in wingless-related integration site (WNT) signaling, we analyzed their interaction patterns with β-catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and β-catenin. TRIB1 (355-DQIVPEY-361), TRIB2 (326-DQLVPDV-332), and TRIB3 (333-AQVVPDG-339) peptides revealed a shallow binding pocket at the COP1 interface to accommodate the V-P sequence motif. Reinvigoration of the comparative binding pattern and subtle structural analysis via docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, topological, and tunnel analysis revealed that both β-catenin phosphodegron (DSGXXS) and TRIB (D/E/ AQXVPD/E) motifs occupied a common COP1 binding site. Current study suggests a structural paradigm of TRIB homologs bearing a conserved motif that may compete with β-catenin phosphodegron signature for binding to WD40 domain of COP1.Thorough understanding of the structural basis for TRIB-mediated regulation of WNT/β-catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers.