Conserved Water Molecule-dependent Docking Strategy and Atom-Based 3D QSAR Studies to Design Heat Shock Protein 90 Inhibitors

Abstract

In this study a methodology was described to recognize the conserved water molecules required for efficient binding of ligands with heat shock protein. Subsequently, a substantiated procedure for the determination of an effective docking methodology was generated using various programs of Schrodinger and SYBYL softwares. In order to identify the essential structural features responsible for heat shock protein inhibitions, an atom based 3D-quantitative structure-activity relationship model with an excellent surmising ability in both external and internal validation was established. The results of 3D-quantitative structure-activity relationship and docking studies correlated well with each other. A combined analysis of docking results and quantitative structure-activity relationship analysis indicates: The key amino acids and water molecules in the active pocket of heat shock protein. The important structural requirement in ligands that will lead to enhanced biological activity. The results provide a set of simple and effective guidelines for rationally designing new heat shock protein inhibitors prior to their synthesis.