Identification of PICK1 PDZ-Domain Antagonists: Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Analyses

PICK1 (protein interacting with C kinase-1) plays a key role in the regulation of intracellular trafficking of AMPA GluA2 subunit that is linked with synaptic plasticity. PICK1 is a scaffolding protein and binds numerous proteins through its PDZ domain. Research showed that synaptic plasticity is altered upon disrupting the GluA2-PDZ interactions. Inhibiting PDZ and GluA2 binding lead to beneficial effects in the cure of neurological diseases thus, preventing PDZ-GluA2 binding is thought to novel therapeutic target in such diseases. To target this, generally, peptides were synthesized and tested. Though small organic molecules have been targeted to prevent these interactions, the number of such molecules is inadequate. Thus, in this study, ten molecular libraries containing large numbers of molecules were screened against the PDZ domain using pharmacophore-based virtual screening to find the best hits for the PDZ domain. Molecular docking and molecular dynamic simulation studies revealed that two hits (Hit_I and Hit_III) show efficient binding to the PDZ domain. This study suggests that tested hits may have potency against the PDZ domain and can be considered effective to treat neurological disorders.