Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε

Abstract

Background: (−)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. Results: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. Conclusions: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.

Identification of Balanol As a Potential Inhibitor of PAK1 That Induces Apoptosis and Cytoprotective Autophagy in Colorectal Cancer Cells

“…Compound 6 was confirmed in previous studies as a competitive inhibitor of PKA and PKC, lacking selectivity. Most researches on compound 6 have focused on improving its selectivity for PKC and PKA, with few studies of its binding to other kinases [38–40] . By molecular docking, MD simulation and CETSA, we confirmed that compound 6 can bind stably to PAK1.…”

“…Most researches on compound 6 have focused on improving its selectivity for PKC and PKA, with few studies of its binding to other kinases. [38][39][40] By molecular docking, MD simulation and CETSA, we confirmed that compound 6 can bind stably to PAK1. More than that, we found that compound 6 can inhibit ERK and AKT, two key signaling pathways downstream of PAK1, in SW480 cells.…”

Exploring the Potency of <i>Nigella sativa</i> Seed in Inhibiting SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations

“…1). Unlike molecular docking, MD simulations allow ligands and M pro to move and interplay, adjusting their intermolecular interactions [23,25]. According to molecular docking results, N3 and leupeptin display two unfavorable interactions with M pro (Table 2, Fig.…”

“…Hence, another method, such as molecular dynamics (MD) simulation, should be implemented after the molecular docking step to obtain a more accurate prediction of energy and conformation. MD simulations have been employed in many studies of protein-ligand interactions [23][24][25].…”

APBioNet's annual International Conference on Bioinformatics (InCoB) returns to India in 2018

“…Bioinformatics provides solutions to predicting the 3D structures of proteins that so not have experimental structures. Hardianto et al [23] have used homology models of novel protein kinase C (PKC) isozymes to characterize their interaction with a candidate inhibitory drug molecule. On the other hand, Borah and Jha [24] have predicted an ab initio structural model for a pathogenic protein, HopS2, that affects tomato plants, to understand its pathogenic function, as a Type III secretion system.…”