QSAR and Pharmacophore Study of Dyrk1A Inhibitory Meridianin Analogs as Potential Agents for Treatment of Neurodegenerative Diseases

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Elevated levels of Dyrk1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. Meridianins are marine derived indole alkaloids exhibiting anti-proliferative activity as well as are known to inhibit panel of kinases. In the present article, a descriptor based QSAR study was carried out for a series of meridianin analogs inhibiting Dyrk1A to find out structural features which are crucial for biological activity. Developed QSAR model showed good correlation coefficient (r > 0.9), higher F value (F > 20) and excellent predictive power (r2 cv and r2 pred > 0.6). Activity of naturally occurring meridianins was also predicted using developed model. The study indicated that kier Chi4 path/cluster, total lipole, VAMP polarization ZZ component, dipole moment Z component and log P plays important role in Dyrk1A inhibition. Further analysis of pharmacophore model using PHASE module of Schrodinger revealed that two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two hydrophobic aromatic rings (R) are crucial molecular features that predict binding affinity for meridianins to the Dyrk1A enzyme. These observations provide important insights to the key structural requirements of meridianins for potent Dyrk1A inhibition. Excellent statistical results of developed models strongly suggest that these models are reasonable for prediction of the activity of new inhibitors and in future drug design.