Hsp90 Inhibitors, Part 2: Combining Ligand-Based and Structure-Based Approaches for Virtual Screening Application

作者：Caroli Antonia; Ballante Flavio; Wickersham Richard B III; Corelli Federico; Ragno Rino^*

来源：Journal of Chemical Information and Modeling, 2014, 54(3): 970-977.

DOI：10.1021/ci400760a

Hsp90 continues to be an important target for pharmaceutical discovery. In this project, virtual screening (VS) for novel Hsp90 inhibitors was performed using a combination of Autodock and Surflex-Sim (LB) scoring. functions with the predictive ability of 3-D QSAR models, previously generated with the 3-D QSAutogrid/R procedure. Extensive validation of both structure-based (SB) and ligand-based (LB), through realignments and cross-alignments, allowed the definition of LB and SB alignment rules. The mixed LB/SB protocol was applied to virtually screen potential Hsp90 inhibitors from the NCI Diversity Set composed of 1785 compounds. A selected ensemble of 80 compounds were biologically tested. Among these molecules, preliminary data yielded four derivatives exhibiting IC50 values ranging between 18 and 63 mu M as hits for a subsequent medicinal chemistry optimization procedure.

• 出版日期2014-3