Current drug targets · 2026
Computational Evaluation of Hydnocarpin as a Novel ROCK2 Inhibitor and Potential Regulator of Mitophagy in Cancer.
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Kaushik Aditi, Shandilya Chesta, Swargiary Geeta, Khan Saboor, Singh Pragya, Gupta Shradheya R R, Singh Indrakant K, Mani Shalini
Аннотация
INTRODUCTION: Impaired mitophagy in cancer cells leads to the accumulation of dysfunctional mitochondria, elevated ROS, and activation of pro-survival pathways, promoting tumour growth and metabolic adaptation. ROCK2, a serine/threonine kinase overexpressed in cancer, negatively regulates Parkin-mediated mitophagy, making it a rational therapeutic target.
METHODS: This study used an integrated in silico pipeline to identify phytocompounds from Indian medicinal plants predicted to inhibit ROCK2 and potentially modulate mitophagy. This study filtered a library of 31,496 natural product compounds from 325 medicinal plants (IMPPAT 2.0 database) using SwissADME based on Lipinski's, Veber's, Ghose's, and Pfizer's rules, yielding 598 drug-like compounds. Bioactivity scoring identified 49 NPCs with kinase inhibitory potential, which underwent Glide SP docking against ROCK2 (PDB: 7JNT), followed by ProTox-II toxicity profiling and XP docking.
RESULTS: Six compounds (Quercetin, Hydnocarpin, Annomontine, Camptothecin, 9- Methoxycamptothecin, and Methoxycamptothecin) showed binding affinities comparable to or exceeding reference inhibitors Fasudil and Y27632, with key interactions at conserved catalytic residues (Met172, Asp218, Asn219, Lys216). MD simulations showed that Hydnocarpin formed the most stable protein-ligand complex, with a consistent RMSD, persistent hydrogen bonding with Glu170, Met172, and Lys216, and minimal residue fluctuations, resembling Fasudil's dynamic profile. Quercetin, despite favourable docking scores, showed structural instability.
DISCUSSION: Integrated docking and MD analyses indicate Hydnocarpin exhibits superior binding stability compared to other screened phytocompounds, suggesting more favourable predicted binding under physiologically relevant simulation conditions.
CONCLUSION: Hydnocarpin emerges as the most promising ROCK2 inhibitor among screened phytocompounds, supporting its potential as a mitophagy-modulating anticancer agent warranting further in vitro validation, as all findings reported here are computational predictions.
METHODS: This study used an integrated in silico pipeline to identify phytocompounds from Indian medicinal plants predicted to inhibit ROCK2 and potentially modulate mitophagy. This study filtered a library of 31,496 natural product compounds from 325 medicinal plants (IMPPAT 2.0 database) using SwissADME based on Lipinski's, Veber's, Ghose's, and Pfizer's rules, yielding 598 drug-like compounds. Bioactivity scoring identified 49 NPCs with kinase inhibitory potential, which underwent Glide SP docking against ROCK2 (PDB: 7JNT), followed by ProTox-II toxicity profiling and XP docking.
RESULTS: Six compounds (Quercetin, Hydnocarpin, Annomontine, Camptothecin, 9- Methoxycamptothecin, and Methoxycamptothecin) showed binding affinities comparable to or exceeding reference inhibitors Fasudil and Y27632, with key interactions at conserved catalytic residues (Met172, Asp218, Asn219, Lys216). MD simulations showed that Hydnocarpin formed the most stable protein-ligand complex, with a consistent RMSD, persistent hydrogen bonding with Glu170, Met172, and Lys216, and minimal residue fluctuations, resembling Fasudil's dynamic profile. Quercetin, despite favourable docking scores, showed structural instability.
DISCUSSION: Integrated docking and MD analyses indicate Hydnocarpin exhibits superior binding stability compared to other screened phytocompounds, suggesting more favourable predicted binding under physiologically relevant simulation conditions.
CONCLUSION: Hydnocarpin emerges as the most promising ROCK2 inhibitor among screened phytocompounds, supporting its potential as a mitophagy-modulating anticancer agent warranting further in vitro validation, as all findings reported here are computational predictions.