title: Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation.
abstract: The pharmacophoric features of the virtual cocrystallized protein of 178 Hsp90 proteins were obtained from the protein data bank and explored to generate 1260 pharmacophores evaluated using the decoy list composed of 1022 compounds. Accordingly, 51 pharmacophores were selected with high receiver operating characteristic (ROC) value for further processing. 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= 0.819, F = 43.0, R2LOO= 0.782, R2PRESSagainst 16 external test inhibitors equal 0.735). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within the Hsp90 binding pocket. The fifth generated pharmacophoric model from Hsp90 protein 2XJX (2XJX_2_05), and the forth generated cocrystallized pharmacophoric model from Hsp90 protein 4LWF (4LWF_2_04) with area under the curve AUC-ROC values 0.812 and 0.876, respectively were selected to be used as a searching tool sequentially of the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best predicted hits were selected. Twenty-four hits showed Hsp90 inhibition, 15 hits were measured with low micromolar IC50ranged from 5.0 μM to 77.1 μM.
authors: a Faculty of Pharmacy , Zarqa University , Zarqa , Jordan and.
authors: Mahmoud A
authors: MA
authors: Al-Sha'er
authors: b Faculty of Pharmaceutical Sciences , the Hashemite University , Zarqa , Jordan.
authors: Iman
authors: I
authors: Mansi
authors: a Faculty of Pharmacy , Zarqa University , Zarqa , Jordan and.
authors: Malak
authors: M
authors: Khanfar
authors: a Faculty of Pharmacy , Zarqa University , Zarqa , Jordan and.
authors: Alaa
authors: A
authors: Abudayyh
mesh_terms: D000465:Algorithms; D003460:Crystallization; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016014:Linear Models
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands
keywords: Co-crystallized structure; Hsp90; NCI; cancer; docking; pharmacophore