Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics

Abstract

Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway.Methods: To acquire details at the molecular level of Indicaxanthin’s inhibitory activity against hIKKβ, molecular modeling and simulation techniques including induced-fit docking (IFD), binding pose metadynamics (BPMD), molecular dynamics simulations, and MM-GBSA (molecular mechanics-generalized Born surface area continuum solvation) have been performed.Results: The computational calculations performed on the active and inactive form, and the allosteric binding site of hIKKβ, revealed that Indicaxanthin inhibits prevalently the active form of the hIKKβ. MM-GBSA computations provide further evidence of Indicaxanthin’s stability inside the active binding pocket with a binding free energy of −22.2 ± 4.3 kcal/mol with respect to the inactive binding pocket with a binding free energy of −20.7 ± 4.7 kcal/mol. BPMD and MD simulation revealed that Indicaxanthin is likely not an allosteric inhibitor of hIKKβ.Conclusion: As a whole, these in silico pieces of evidence show that Indicaxanthin can inhibit the active form of the hIKKβ adding novel mechanistic insights on its recently discovered ability to impair NF-κB signaling in melanoma A375 cells. Moreover, our results suggest the phytochemical as a new lead compound for novel, more potent IKKβ inhibitors to be employed in the treatment of cancer and inflammation-related conditions.

Indicaxanthin from Opuntia ficus-indica Fruit Ameliorates Glucose Dysmetabolism and Counteracts Insulin Resistance in High-Fat-Diet-Fed Mice

“…In terms of biochemical mechanisms, disruption of glucose homeostasis can be envisaged as the result of a self-feeding cycle between systemic, chronic inflammation and oxidative stress, initiated by excess nutrient consumption. Along these lines, one potential explanation for the beneficial effects of indicaxanthin supplementation on insulin sensitivity may lie in its anti-inflammatory properties [ 25 , 26 , 28 , 54 , 55 ].…”

“…Along these lines, significant reducing, anti-oxidative, anti-inflammatory, anti-proliferative, anti-tumoral, spasmolytic and neuromodulatory and neuroprotective [ 24 ] effects of indicaxanthin have been reported both in vitro and in vivo [ 21 ]. Interestingly, NF-κB has been proposed as one of the crucial molecular targets that indicaxanthin can interact with, to exert its anti-inflammatory effects [ 25 , 26 , 27 , 28 , 29 ].…”

Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones

“…To further assess the reliability of the obtained results and to confirm the stability of the system, we combined the docking protocols with molecular dynamics (MD) simulation techniques to study conformational changes in the ligand–receptor complex over simulation time [ 45 , 46 ]. Simulations provide every minute detail about every atom movement with respect to time and can help in answering questions arising on the deviation and fluctuation pattern of protein.…”

In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

“…The structure was optimized using the Protein Preparation Wizard in Maestro (Schrödinger, 2021-1) adding bond orders and hydrogen atoms to the crystal structure using the OPLS4 force field. The remaining settings are reported in [79].…”

“…Protein-ligand binding free energy using MM-GBSA was calculated as the difference between the energy of the bound complex and the energy of the unbound protein and ligand. The entropy term −T∆S was not calculated to reduce computational time as previously reported [79,[81][82][83]. The VSGB solvation model was chosen using OPLS4 force field with the minimized sampling method.…”