Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

<p>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 (<i>R₆₇²</i> = 0.819, <i>F</i> = 43.0, <i>R</i>²_LOO= 0.782, <i>R</i>²_PRESS against 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 (<b>2XJX_2_05</b>), and the forth generated cocrystallized pharmacophoric model from Hsp90 protein 4LWF (<b>4LWF_2_04</b>) 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 IC₅₀ ranged from 5.0 μM to 77.1 μM</p

Novel hydantoin derivatives: Synthesis and biological activity evaluation

Novel compounds derived from hydantoin were synthesized using a chloroacetyl chloride linker in conjunction with terminal compounds of sulphonamides and amines. The compounds were subjected to various analytical techniques, including LC-MS/MS, 1H NMR, 13C NMR, FT-IR, and determination of melting point. Subsequently, the synthesized compounds were evaluated for their potential anti-cancer properties (against) breast cancer (MCF-7) and lung cancer (A549) cell lines by the MTT assay. Additionally, the compounds' anticonvulsant activity was assessed using pentylenetetrazol (PTZ)-induced seizure in mice. Furthermore, the inhibitory activity of selected compounds against the PI3Kα enzyme at a concentration of 100 µM was investigated. The biological evaluation of the compounds did not show the expected anticonvulsant effect when tested at various doses (5, 10, and 20 mg/kg b.w using the intraperitoneal injection), with all mice showing a seizure score of 5. MTT assay showed moderate anti-cancer activity against, the (A549) cell line, with compound 37 exhibiting the highest inhibition of cell viability at 55.1%. In the case of the breast cancer cell line, compounds 37, 40, 42, and 45 demonstrated inhibition percentages ranging from 64% to 74%. Moreover, the compounds displayed a relatively limited inhibitory effect on PI3Kα activity during the in-vitro evaluation compared to staurosporine. These findings suggest that further optimization and modification of the synthesized compounds may be necessary to enhance their anticonvulsant and anti-cancer properties, particularly regarding PI3Kα inhibition