GRP78-targeted in-silico virtual screening of novel anticancer agents.

Overexpression of GRP78 in a variety of cancers such as glioblastoma, leukemia, lung, prostate, breast, gastric, and colon makes it a prime target for anticancer drug development. Present study reports GRP78-based design of novel anticancer agents using in-silico methods. As a first step toward the work, the interactions between GRP78 and 15 known ligands were modeled by docking simulation. The docked complex, GRP78-13, superior to other compounds with respect to its experimental activity and energy descriptors, was deduced into a structure-based pharmacophore. This hypothesis was applied as a screening filter to Asinex and Chemdiv databases. Finally, 23 hits were tested in vitro. Among these, VH1019 and VH1011 induced a concentration-dependent strong broad antiproliferative effect in glioma (U87-MG), breast cancer (MCF-7), and prostate cancer (DU-145) cell lines as compared to nontumorigenic control, neonatal foreskin fibroblast (HFF-1). These compounds showed preferential growth inhibition of cancer cells over normal cells. The acetohydrazide derivative VH1019 was identified as a potential new chemotype for GRP78 inhibitors with an IC50 of 12.7 µM in MCF-7.

In silico-designed novel non-peptidic ABAD LD hot spot mimetics reverse Aß-induced mitochondrial impairments in vitro.

Present work aimed to introduce non-peptidic ABAD loop D (LD ) hot spot mimetics as ABAD-Aß inhibitors. A full-length atomistic model of ABAD-Aß complex was built as a scaffold to launch the lead design and its topology later verified by cross-checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Aß-binding LD residues-Tyr101, Thr108, and Thr110-were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA-based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC50 of 4.4 ± 0.3 and 9.6 ± 0.1 µm, respectively. They productively reversed Aß-induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC-1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of LD hot spot-centric in silico scheme to discover novel compounds with promising ABAD-Aß inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics.

Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking.

Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 µM, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity.

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC50 values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.

Psoralidin, a coumestan analogue, as a novel potent estrogen receptor signaling molecule isolated from Psoralea corylifolia.

A novel biological activity of psoralidin as an agonist for both estrogen receptor (ER)α and ERß agonist has been demonstrated in our study. Psoralidin has been characterized as a full ER agonist, which activates the classical ER-signaling pathway in both ER-positive human breast and endometrial cell lines as well as non-human cultured cells transiently expressing either ERα or ERß. The estrogenic activity was determined using the relative expression levels of either reporter or the endogenous genes dependent on the agonist-bound ER to the estrogen response element (ERE). Psoralidin at 10 µM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of psoralidin are mediated by ER. Psoralidin was also able to induce the endogenous estrogen-responsive gene, pS2, in human breast cancer cells MCF-7. It was observed that activation of the classical ER-signaling pathway by psoralidin is mediated via induction of ER conformation by psoralidin and direct binding of the psoralidin-ER complex to the EREs present in the promoter region of estrogen-responsive genes, as shown by chromatin immunoprecipitation assay results. Finally, molecular docking of psoralidin to the ligand binding pocket of the ERα showed that psoralidin is able to mimic the binding interactions of E2, and thus, it could act as an ER agonist in the cellular environment.