Unraveling the Molecular Inhibition and Conformational Changes of Hsp70 and Hsc70 Induced by VER-155008, a Competitive ATPase Inhibitor through Molecular Dynamics Simulations and Principal Component Analysis

The heat shock protein 70 kDa (Hsp70) is critical for the survival of cancer cells, playing a role in developing chemotherapy resistance, since it inhibits apoptosis of these cells and ensures their survival in stressful environments. Due to its structural similarity with heat shock cognate 70 kDa (Hsc70), the design of new selective Hsp70 inhibitors presents significant challenges. Previous studies have reported that the molecule VER-155008 functions as a nonselective inhibitor of Hsp70 by binding to the nucleotide-binding domain of both proteins, thereby acting as a competitive inhibitor of adenosine triphosphate (ATP) binding. In the present study, molecular dynamics (MD) simulations and free energy landscape (FEL) analysis were used to investigate the conformational dynamics of Hsp70 and Hsc70 with the competitive ATPase inhibitor VER-155008, revealing its binding mechanism and its role in inducing a half-open conformation that inhibits ATP binding. Our findings highlight key residues Ser275, Lys271, and Glu268 involved in the stabilization of the inhibitor binding and some conformational states in both proteins due to the inhibitor binding, explaining molecular characteristics that could be used to develop new selective inhibitors at the nucleotide binding site of Hsp70, thus aiming to advance the development of targeted therapies in cancer treatment.