In silico prediction, molecular docking, and dynamics analysis of steroidal alkaloids from the genus Fritillaria: implications for designing novel antiparkinsonian therapeutic strategies

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting nearly 0.3% of the global population. Its pathology is primarily linked to dopaminergic neuronal loss in the substantia nigra, leading to hallmark motor impairments such as tremor, rigidity, and bradykinesia. A defining molecular feature of PD is the aberrant aggregation of α-synuclein, alongside dysregulation of proteins such as MAO-B, COMT, and LRRK2, which collectively contribute to disease progression. Within the current research, these proteins were designated as docking targets to explore the enzyme-modulating activity and the therapeutic promise of steroidal alkaloid candidates from the genus Fritillaria, a taxon long recognized in traditional medicine for its neuroprotective properties. Docking analyses revealed that among 70 compounds analysed, compound 65 exhibited strong MAO-B inhibitory activity (binding energy - 11 kcal/mol), compound 5 demonstrated pronounced COMT inhibition (- 9 kcal/mol), and compound 42 emerged as a promising dual-acting agent capable of targeting both enzymes. Favorable physicochemical attributes, including optimal lipophilicity, low polar surface area, and blood-brain barrier permeability, further support their suitability. These findings identify preliminary computational leads that warrant further experimental validation for potential future development.