Structure-Based Virtual Screening Identifies 2-Arylthiazole-4-Carboxylic Acids as a Novel Class of Nanomolar Affinity Ligands for the CaMKIIα Hub Domain

Abstract

The Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) plays a crucial role in regulating neuronal signaling and higher brain functions, being involved in various brain diseases. Utilization of small molecules targeting the CaMKIIα hub domain has proved to be a promising strategy for specific CaMKIIα modulation and future therapy. Through an in silico structure-based virtual screening campaign, we herein identified 2-arylthiazole-4-carboxylic acids as a new class of high-affinity CaMKIIα hub ligands. Particularly, the 2,6-dichlorophenyl analog, PTCA (compound 1a), displayed mid-nanomolar affinity (pK_i = 7.2) and substantial stabilization of the CaMKIIα hub oligomer upon binding. Moreover, the tert-butyl ester prodrug, 14a, was developed to facilitate the brain delivery of PTCA and demonstrated remarkable enhancement in brain penetration compared to PTCA per se after systemic administration. Altogether, our study highlights that PTCA represents a novel and powerful tool compound for future pharmacological interventions targeting CaMKII kinase in the brain.