# 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

## TL;DR

This study explores how the drug VER-155008 inhibits Hsp70 and Hsc70 proteins, causing conformational changes that could help develop better cancer treatments.

## Contribution

The study reveals the molecular mechanism of VER-155008-induced conformational changes in Hsp70 and Hsc70 using MD simulations and FEL analysis.

## Key findings

- VER-155008 induces a half-open conformation in Hsp70 and Hsc70, inhibiting ATP binding.
- Key residues Ser275, Lys271, and Glu268 stabilize inhibitor binding and conformational states.
- Findings suggest molecular features for designing selective Hsp70 inhibitors.

## Abstract

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.