AMPA GluA2 subunit competitive inhibitors for PICK1 PDZ domain: Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and ADME studies.

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, targeting PDZ domain is proposed as a novel therapeutic target in such diseases. For this, various classes of synthetic peptides were tested. Though small organic molecules have been utilized to prevent these interactions, the number of such molecules is inadequate. Hence, in this study, ten molecular libraries containing large number 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 dynamics simulation studies revealed that Hit_II is a potent inhibitor for the PDZ domain and confirm the allosteric nature of Hit_III. Additionally, ADME analysis suggests the drug-likeness of both Hit_II and Hit_III. This study suggests that tested hits may have potency against the PDZ domain and can be considered effective to treat neurological disorders.Communicated by Ramaswamy H. Sarma.