Structural Insight Into Protein Kinase D Small Molecule Inhibition

摘要: Protein kinase D (PKD) is a family of serine/threonine kinases that has emerged as novel therapeutic target in multiple diseases; therefore, the development small molecule inhibitors abrogate PKD’s function been an area intense investigation. However, these efforts have not yet resulted PKD available for clinical applications. Access to structural information can greatly accelerate this drug discovery process and allow future initiatives benefit from structure-based design. Therefore, we employed both computational experimental methods investigate important characteristics excellent potency selectivity. We found type I ATP-competitive bind hinge region position hydrogen bond acceptor near charged side chain Lys612. An additional moiety (typically basic amino group) capable developing critical salt bridge with Glu710 was shown be improved affinity. Further analysis inhibitor selectivity profiles suggested strategic functionalization pocket II could potentially reduce off-target effects. From our investigation CRT0066101 inhibition, developed chemical genetic tool kit evaluating function. Mutating gatekeeper residue, Met659, phenylalanine or tyrosine dramatically sensitized inhibition. Conversely, mutating G664, valine isoleucine conferred resistance. Taken together, study provides key insights into features associated which will aid therapeutic.