Molecular dynamic investigation for ROCO-4 kinase inhibitor as treatment options for parkinsonism

Abstract

Parkinsons disease (PD) is a neurodegenerative condition that degenerates dopaminergic neurons and is characterized by motor disabilities like rigidity, bradykinesia, postural instability, and resting tremors. Although the etiology of PD remains uncertain, familial and sporadic forms of PD are known to be predominately caused by the G2019S mutation present in the kinase domain of LRRK2. Therefore, it might be possible to treat Parkinsons by inhibiting the kinase action of the mutated LRRK2 protein. In order to find possible inhibitors, 3069 phytochemicals were examined for their ability to bind ROCO4 kinase, which has structural and functional similarities to the LRRK2 protein. Open-source bioinformatics tools were used to determine the binding affinities of phytochemicals to the native and mutant variants of the protein. Mongolicain-A exhibited high specificity and selectivity towards the G2019S mutation of the ROCO4 protein with -12.3 Kcal/mol binding affinity, whereas Bacoside-A displayed high affinity (11.4 Kcal/mol) for the target protein, but lacked specificity towards the mutant form of the protein. Based on molecular simulation studies., RMSD, RMSF, SASA, potential energy, and hydrogen bond analysis, it was suggested that Mongolicain-A may be an effective inhibitor of the G2019S mutation and a promising drug molecule to address PD.