Hsp90 Inhibitors (I). Definition of 3-D QSAutogrid/R Models as a Tool for Virtual Screening

The multi-chaperone 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 anti-cancer 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- and structure-based (LB/SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, 8 SB PLS 3-D QSAR models were generated, leading to a final multi-probe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for HSP90 inhibition. Both the mono-probe and multi-probe 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.