Background: Berberine, a naturally occurring alkaloid, is widely explored for several health benefits, including weight management and metabolic disorders. The major pharmacological action of berberine is reported to be by activation of AMP-activated protein kinase, while its other clinical outcomes are devoid of clear mechanism of action/s. Hence in this study a detailed pharmacology of berberine and its two major metabolites (berberrubine, and jatrorrhizine) in humans was evaluated using well established Insilco tools. Materials and Methods: The targets of berberine and its metabolites were identified in SwissTargetPrediction server and their affinity was assed using AutoDock vina 1.2.0. The binding pockets of the highest ligand receptor combinations was assessed using the PrankWeb: Ligand Binding Site Prediction tool. Results: Kinases, enzymes and family A GPCR’s were identified as the top three target category of berberine and its metabolites. ROCK2, PIK3CD, KCNMA1, CSF1R, and KIT were observed to be the high affinity targets of berberine and its metabolites with affinity values of <4 uM. The affinity of berberine and its metabolites against all AMPKs and lipid/glucose regulator targets (LDLR, DDP4 and PCSK9) were >10 uM. The IC50 value of berberine and its metabolites against ROCK2 was the least (<1 uM), while their other high affinity targets (PIK3CD, KCNMA1, CSF1R and KIT) showed IC50 values <5 uM. Conclusion: The diverse range of protein targets and the observed novel high affinity targets (ROCK2, PIK3CD, KCNMA1, CSF1R and KIT) offer valuable insights into the potential mechanisms of action and therapeutic effects of berberine and its metabolites in various disease conditions, which warrants validation in suitable efficacy analysis studies.

Berberine, Berberrubine, Jatrorrhizine, Cancer, Diabetes, Obesity, Mechanisms, Pharmacodynamics