Elaborate Ligand-Based Modeling Reveals New Nanomolar Heat Shock Protein 90α Inhibitors

Heat shock protein (Hsp90α) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90α inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90α inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure−activity relationship (QSAR) of optimal predictive potential (r672 = 0.811, F = 42.8, rLOO2 = 0.748, rPRESS2 (against 16 external test inhibitors) = 0.619). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the Hsp90α binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds and our in-house-built drugs and agrochemicals database (DAC). Twenty-five nanomolar and low micromolar Hsp90α inhibitors were identified. The most potent were formoterol, amodaquine, primaquine, and midodrine with IC50 values of 3, 5, 6, and 20 nM, respectively.