ABSTRACT: The p21-activated kinase 2 (PAK2), a serine/threonine kinase, directly participates in the regulation of various cellular signaling pathways and plays a critical role in cell motility, survival, and proliferation. Due to its crucial role in cell signaling pathways, cytoskeletal organization, and cell survival, PAK2 has emerged as a promising drug target, especially in cancer and cardiovascular diseases. However, systematic studies examining PAK2 inhibition are still limited, and an effective inhibitor has proven quite challenging to develop. Existing drug discovery methods are labor-intensive and expensive. Therefore, new approaches like drug repurposing are required. Here, we employed a systematic, structure-based drug repurposing strategy to identify potential repurposed inhibitors of PAK2 from a library of FDA-approved drug molecules. Structure-based virtual screening of 3648 FDA-approved compounds led to the identification of Midostaurin and Bagrosin as top-hit candidates with predicted potency against PAK2, due to their high binding affinity and specificity to the PAK2 active site. Additional interaction analysis obtained from molecular docking suggested that stable hydrogen bonds were formed between Midostaurin and Bagrosin with key PAK2 residues, leading us to propose an inhibitory role. To ensure stability and interaction dynamics, a molecular dynamics (MD) simulation was conducted for 300 ns, demonstrating good thermodynamic properties for the stable binding of Midostaurin and Bagrosin to PAK2, in comparison to a control inhibitor, IPA-3. Although these results are encouraging, the study only yielded in silico data, and further experimental evaluation will be necessary to validate the inhibition of PAK2 by Midostaurin and Bagrosin. However, our results provide valuable insights for the future development of PAK2 inhibitors and underscore the importance of repurposed drugs in cancer therapy. Comparative docking and selectivity profiling also suggest that these compounds preferentially target PAK2 over other isoforms such as PAK1 and PAK3, warranting further experimental validation.
