Plant Compounds Emerge as Potential Dual Blockers of Brain-Damaging Enzymes

Neurons are among the most energy-hungry cells in the human body, and their survival depends on a constant, finely balanced supply of healthy mitochondria. When these power plants malfunction, the consequences ripple outward: synaptic transmission falters, reactive oxygen species accumulate, and inflammatory cascades ignite in brain tissue. A new computational study published in the journal Neuroinformatics by Chesta Shandilya and Shalini Mani of Jaypee Institute of Information Technology in Noida, India, suggests that a familiar family of plant-derived chemicals may hold the key to restoring that balance. By screening hundreds of natural compounds from Indian medicinal plants against two enzymes implicated in neurodegeneration, the researchers identified several molecules capable of binding both targets, with one compound in particular, coumarin, standing out as a stable, brain-penetrant dual inhibitor.

The enzymes in question are the Rho-associated coiled-coil kinases, ROCK1 and ROCK2, which have emerged in recent years as critical upstream regulators of mitochondrial behavior in neurons. ROCK1 promotes Drp1-mediated mitochondrial fission, the process by which mitochondria split into daughter organelles. While some fission is essential for cellular housekeeping, excessive fission fragments the mitochondrial network and contributes to neuronal death, a mechanism documented in Parkinson’s disease where ROCK1 activation drives dopaminergic cell apoptosis. ROCK2, by contrast, suppresses the PINK1-Parkin pathway, the cellular machinery responsible for identifying damaged mitochondria and tagging them for destruction through mitophagy. When ROCK2 is overactive, worn-out mitochondria linger in the cell, spewing reactive oxygen species and draining ATP reserves.

Overexpression of both ROCK isoforms, the researchers note, leads to increased ROS production and reduced ATP generation, a double blow that compromises neuronal health and fuels the neuroinflammation characteristic of Alzheimer’s, Parkinson’s, and related disorders. Synthetic ROCK inhibitors such as fasudil have shown neuroprotective potential in animal models, reducing amyloid-beta production and improving proteomic profiles in Alzheimer’s mice. Yet their translation into long-term therapy for chronic neurological disease has been hampered by toxicity concerns, poor pharmacokinetics, and suboptimal penetration of the blood-brain barrier, the selective border that shields the brain from most circulating molecules.

Natural compounds offer a compelling alternative. Plant-derived phytochemicals are often cheaper to produce, generally better tolerated, and in some cases possess scaffolds optimized by evolution for biological activity. To explore this possibility systematically, Shandilya and Mani turned to the pharmacopeia of Indian traditional medicine. Drawing on documented neuroprotective properties and underexplored mechanisms of action, they selected eleven medicinal plants, including species such as Convolvulus pluricaulis, Centella asiatica, Alpinia galanga, and Evolvulus alsinoides, all of which have been studied for cognitive and neuroprotective effects in preclinical work.

From these plants, the team assembled a virtual library of 1,223 natural product compounds, which was then curated down to 428 unique phytocompounds for screening. A known ROCK inhibitor was included as a reference benchmark. The screening pipeline followed the standard architecture of modern computational drug discovery: molecular docking to predict how each compound fits into the ATP-binding pockets of ROCK1 and ROCK2, followed by successive layers of increasingly rigorous validation designed to weed out false positives.

Several natural phytocompounds achieved binding affinities comparable to the reference inhibitor, demonstrating that plant chemistry can compete with synthetic medicinal chemistry at these targets. The shortlist was then subjected to pharmacokinetic profiling and toxicity classification to assess drug-likeness, absorption, and safety liabilities. MM-GBSA calculations provided estimates of free binding energy in a more realistic solvent environment than docking alone, and finally, molecular dynamics simulations running for 200 nanoseconds tested whether the predicted complexes remained stable when the proteins were allowed to flex and move in water, as they do in living cells.

The results converged on a handful of standout molecules. Scopolin and lycorine emerged as promising ROCK1 inhibitors, the isoform responsible for driving pathological mitochondrial fission. Cytisoside and N-methyltyramine demonstrated strong inhibition of ROCK2, the suppressor of PINK1-Parkin mitophagy. Each of these compounds could, in principle, address one half of the mitochondrial quality-control problem: either curbing excessive fission or releasing the brake on damaged-mitochondria removal.

The most intriguing finding, however, was coumarin. This simple benzopyrone, found in many plants including several of the species screened, exhibited stable and persistent interactions with both ROCK1 and ROCK2 across the full simulation window. It combined good binding energies with high predicted blood-brain barrier permeability, addressing one of the major failings of existing synthetic inhibitors, and maintained strong dynamic stability in the 200-nanosecond trajectories, suggesting the interactions are not artifacts of a static protein structure. A dual inhibitor is particularly attractive because mitochondrial fission and mitophagy are mechanistically linked: fission facilitates the selective autophagy of damaged organelles, so a single molecule that rebalances both arms of the pathway could restore mitochondrial quality control more coherently than two separate drugs.

The authors are careful to frame these findings as a starting point rather than a therapeutic endpoint. In-silico screening, however sophisticated, generates hypotheses that must survive contact with biology. The study concludes that coumarin’s potential to restore the balance between mitochondrial fission and mitophagy, and thereby mitigate neurodegenerative disease, should be validated using in vitro assays, where the compounds can be tested against living neurons and measured for their actual effects on Drp1 recruitment, PINK1-Parkin signaling, ROS levels, and ATP production. Pharmacokinetic predictions also require laboratory confirmation, since computational models of blood-brain barrier penetration are approximations.

Even so, the work illustrates how neuroinformatics is reshaping the search for neuroprotective drugs. Rather than screening millions of synthetic molecules at enormous cost, researchers can now mine the accumulated ethnopharmacological knowledge of traditional medicine systems, filter it through structure-based computation, and arrive at a small set of testable candidates within months. If coumarin and its fellow phytocompounds perform well in cellular and animal models, they could open a path toward safer, cheaper, and more brain-accessible therapies for diseases that currently have few options capable of slowing their progression. For now, the mitochondria of neurons under threat have gained a new set of molecular allies, at least on the computer screen.

Subject of Research: In-silico screening of natural phytocompounds as ROCK1 and ROCK2 inhibitors to modulate mitochondrial fission and mitophagy in neurological diseases

Article Title: Targeting ROCK Isoforms by Natural Phytocompounds: An In-Silico Approach to Modulate Mitochondrial Fission and Mitophagy in Neurological Diseases

Article References: Shandilya, C., & Mani, S. (2026). Targeting ROCK Isoforms by Natural Phytocompounds: An In-Silico Approach to Modulate Mitochondrial Fission and Mitophagy in Neurological Diseases. Neuroinformatics, 24(4), Article 67. https://doi.org/10.1007/s12021-026-09822-0

Image Credits: AI Generated

DOI: 10.1007/s12021-026-09822-0

Keywords: ROCK1, ROCK2, mitochondrial fission, mitophagy, phytocompounds, coumarin, neurodegenerative diseases, molecular docking, molecular dynamics, Indian medicinal plants, blood-brain barrier, neuroinformatics