Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.

Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

Embryo-feto-toxicity of anticancer drug, heptaplatin in laboratory mice.

The present study was conducted to test the possible teratogenic and toxic effects of anti-cancer drug heptaplatin (SKI 2053) on developing embryos and fetuses in gestating SWR/J mice. Dose levels of 5.0, 10.0 and 12.5 mg heptaplatin/kg b.wt. were intraperitoneally administered to pregnant mice on days 6-8, 9-11 and 12-14 of gestation. On day 17 of gestation, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) by taking observation on live fetuses and embryonic resorption. Fetuses were also examined for external, internal and skeletal malformations. None of the dams treated with heptaplatin at any of the dose levels used in the present study died during the experimental period. Higher doses of heptaplatin caused greater embryonic resorption and reduced number of live fetuses. However, no loss of body weight was noticed in fetuses at any of the dose levels administered. At highest dose of heptaplatin (12.5 mg kg(-1)), tail deformity was observed in the form of short and curve tails whereas no other anatomical or skeletal malformations were noticed in any of the fetuses. In addition to mild embryo-fetotoxicity, the study indicates mild teratogenic effects of hetaplatin as reflected in fetal abnormalities at low frequency. These results have significant implications for protracted use of this drug.