Precise design of highly isoform-selective p21-activated kinase 4 inhibitors: computational insights into the selectivity mechanism through molecular dynamics simulation and binding free energy calculation

Understanding the selectivity mechanisms of inhibitors towards highly similar protein kinases is the first step in discovering new selective candidate for satisfactory safety profile. P21-activated kinases (PAKs) are pertain to a family of serine/threonine (Ser/Thr) protein kinases, which are the first Rho family GTPase-regulated kinases identified and served as important downstream mediators of Ras-Rac and Cdc42 function. Among PAKs, PAK4 is emerging as a promising target for cancer treatment. Since the PAK2 inhibition correlates with increased acute cardiovascular toxicity, which may be enhanced by PAK1 inhibitor, selective inhibition of PAK4 over PAK1 is crucial in discovering safe anticancer candidates with optimal therapeutic efficacy. While the conserved ATP-binding pockets of both PAK1/4 make it challenging to discriminating selective inhibitors between PAK1 and PAK4, thus the selectivity mechanism of PAK1/4 inhibitors will be explored in this present study through, computational strategies which combine molecular docking, structural comparison, molecular dynamics simulation and molecular mechanics/generalized Born surface area calculation. The research would provide valuable insight into the selectivity mechanism of PAK4 inhibitors over PAK1 and thus be helpful for designing selective PAK4 inhibitors. Communicated by Ramaswamy H. Sarma