In Silico Identification Of Novel Small Molecules Similar To Ripasudil Targeting Rock2 Enzyme For Corneal Endothelial Recovery Following Cataract Surgery

Corneal endothelial cell loss after cataract surgery can lead to postoperative corneal edema and delayed visual recovery. ROCK2 signaling plays a key role in endothelial cytoskeletal regulation, migration, and contact inhibition. Ripasudil, a ROCK inhibitor, has demonstrated endothelial protective and regenerative effects. This study aimed to identify novel small molecules structurally similar to ripasudil with potential ROCK2 inhibitory activity using a computer-aided drug discovery (CADD) framework.

This computational drug discovery study conducted at a tertiary academic center of coastal Odisha in India. The workflow integrated ligand-based and structure-based approaches. 

Ripasudil was retrieved from PubChem and used as a reference for similarity screening in PubChem chemical library. Molecular fingerprints and Tanimoto similarity coefficients (90%) were applied to identify candidate analogs. Pharmacophore modeling was employed to highlight essential functional groups. Molecular docking studies were performed against high-resolution ROCK2 crystal structures obtained from the Protein Data Bank, followed by docking to evaluate binding affinity. In silico ADMET and drug-likeness predictions were conducted to evaluate pharmacokinetic and toxicity profiles of top-ranking 20 hits.Top molecule amongst them with good safety profile underwent  molecular dynamics (MD) simulations to assess complex stability. 

633 similar molecules were found. 178 ripasudil analogs demonstrated favorable docking scores and stable interactions with the ATP-binding site of ROCK2, comparable or superior to the reference ligand. ADMET predictions of best 20 molecules suggested acceptable oral bioavailability and low toxicity risks. MD simulations confirmed consistent binding stability of 6-[[(2R)-2-methyl-1,4-diazecan-1-yl]sulfonyl]isoquinoline. 

This study highlights the potential of CADD methodologies to accelerate the discovery of novel ROCK2 inhibitors for glaucoma management. The identified ripasudil-derived analogs represent promising leads for further optimization and experimental validation toward next-generation endothelial regeneration therapeutics.