Targeting TNBC metastasis: In-silico identification of natural origin ROCK inhibitors via virtual screening, ADMET profiling, MM-GBSA, DFT, and molecular dynamics

Objective

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by lower survival and over 90 % of deaths from metastases. Rho-associated coiled-coil kinase (ROCK) plays a key role in TNBC progression by regulating cell motility and invasion. This study aims to identify novel ROCK inhibitors of natural origin that may suppress metastasis in TNBC, leveraging a computational drug discovery approach.

Methods

The Coconut database (1,23,971 natural compounds) was utilized for virtual screening. Further pharmacokinetic and pharmacodynamic properties were predicted using the SMARTCyp web server and the Schrodinger suite QikProp module. The top-ranking hits were further investigated using MM-GBSA binding free energy calculations, DFT analysis for electronic property evaluation, and MD simulations to assess structural stability and dynamic behavior of the ligand–protein complexes.

Results

Natural compounds (CNP0115371, CNP0232719, CNP0328678, CNP0182511, and CNP0108029) predicted to exhibit strong ROCK binding affinity (-13.18 to −12.04 kcal/mol), favorable ADMET properties, and stable interaction profiles. DFT calculations revealed high chemical reactivity and electron distribution suitable for biological interaction. MD simulations confirmed stable protein-ligand interactions over a 100-ns trajectory, supporting the compounds' potential as ROCK inhibitors. The study identified five promising naturally origin compounds as potential ROCK inhibitors with anti-metastatic relevance for TNBC treatment. These findings need further experimental validation to confirm their therapeutic efficacy and develop novel anti-TNBC agents from natural origins.