Hsp90 Inhibitors, Part 1: Definition of 3‑D QSAutogrid/R Models as a Tool for Virtual Screening

The
multichaperone heat shock protein (Hsp) 90 complex mediates
the maturation and stability of a variety of oncogenic signaling proteins.
For this reason, Hsp90 has emerged as a promising target for anticancer
drug development. Herein, we describe a complete computational procedure
for building several 3-D QSAR models used as a ligand-based (LB) component
of a comprehensive ligand-based (LB) and structure-based (SB) virtual
screening (VS) protocol to identify novel molecular scaffolds of Hsp90
inhibitors. By the application of the 3-D QSAutogrid/R method, eight
SB PLS 3-D QSAR models were generated, leading to a final multiprobe
(MP) 3-D QSAR pharmacophoric model capable of recognizing the most
significant chemical features for Hsp90 inhibition. Both the monoprobe
and multiprobe models were optimized, cross-validated, and tested
against an external test set. The obtained statistical results confirmed
the models as robust and predictive to be used in a subsequent VS.