A computational study to target necroptosis via RIPK1 inhibition

Bepari, Asim Kumar; Takebayashi, Hirohide; Namme, Jannatun Nayem; Rahman, Ghazi Muhammad Sayedur; Reza, Hasan Mahmud

doi:10.1080/07391102.2022.2108900

Cited by 1 publication

(3 citation statements)

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“…To validate RIPK1 interactions with the top three ligands, we performed replicated 500-ns MD simulations using Gromacs. As described previously, the co-crystallized ligand L8D in 6NYH was a positive control for the inhibition of RIPK1 ( Bepari et al, 2022 ). RIPK1 complexes with the ligands were placed in an octahedral box, which we solvated with water and then neutralized the system with KCl.…”

Section: Resultsmentioning

confidence: 99%

“…We downloaded a 3D structure of the human RIPK1 from the RCSB Protein Data Bank (PDB ID: 6NYH). In a previous study, we used this pdb file for molecular docking ( Bepari et al, 2022 ). The x-ray crystal structure has a resolution of 2.10 Å.…”

Section: Methodsmentioning

confidence: 99%

“…We adopted the docking protocols from a previous study ( Bepari et al, 2022 ). We utilized a 26*26*26 Å gridbox, centered at the XYZ coordinates −17.094, 13.895, and −37.761, corresponding to the center of the reference ligand L8D in 6NYH.…”

Section: Methodsmentioning

confidence: 99%

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Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Bepari,

Shatabda,

Reza

2024

PeerJ

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Background Global prevalence of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease is increasing gradually, whereas approvals of successful therapeutics for central nervous system disorders are inadequate. Accumulating evidence suggests pivotal roles of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in modulating neuroinflammation and necroptosis. Discoveries of potent small molecule inhibitors for RIPK1 with favorable pharmacokinetic properties could thus address the unmet medical needs in treating neurodegeneration. Methods In a structure-based virtual screening, we performed site-specific molecular docking of 4,858 flavonoids against the kinase domain of RIPK1 using AutoDock Vina. We predicted physicochemical descriptors of the top ligands using the SwissADME webserver. Binding interactions of the best ligands and the reference ligand L8D were validated using replicated 500-ns Gromacs molecular dynamics simulations and free energy calculations. Results From Vina docking, we shortlisted the top 20 flavonoids with the highest binding affinities, ranging from −11.7 to −10.6 kcal/mol. Pharmacokinetic profiling narrowed down the list to three orally bioavailable and blood-brain-barrier penetrant flavonoids: Nitiducarpin, Pinocembrin 7-O-benzoate, and Paratocarpin J. Next, trajectories of molecular dynamics simulations of the top protein-ligand complexes were analyzed for binding interactions. The root-mean-square deviation (RMSD) was 1.191 Å (±0.498 Å), 1.725 Å (±0.828 Å), 1.923 Å (±0.942 Å), 0.972 Å (±0.155 Å) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The radius of gyration (Rg) was 2.034 nm (±0.015 nm), 2.0.39 nm (± 0.025 nm), 2.053 nm (±0.021 nm), 2.037 nm (±0.016 nm) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The solvent accessible surface area (SASA) was 159.477 nm2 (±3.021 nm2), 159.661 nm2 (± 3.707 nm2), 160.755 nm2 (±4.252 nm2), 156.630 nm2 (±3.521 nm2), for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D complexes, respectively. Therefore, lower RMSD, Rg, and SASA values demonstrated that Nitiducarpin formed the most stable complex with the target protein among the best three ligands. Finally, 2D protein-ligand interaction analysis revealed persistent hydrophobic interactions of Nitiducarpin with the critical residues of RIPK1, including the catalytic triads and the activation loop residues, implicated in the kinase activity and ligand binding. Conclusion Our target-based virtual screening identified three flavonoids as strong RIPK1 inhibitors, with Nitiducarpin exhibiting the most potent inhibitory potential. Future in vitro and in vivo studies with these ligands could offer new hope for developing effective therapeutics and improving the quality of life for individuals affected by neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%