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Type II diabetes is an endemic disease and is responsible for approximately 90% to 95% of diabetes cases. The pathophysiological distortions are majorly β-cell dysfunction, insulin resistance, and long-term inflammation, which all progressively unsettle the control of blood glucose levels and trigger microvascular and macrovascular complications. The diverse pathological disruptions which patients with type II diabetes mellitus exhibit precipitate the opinion that different antidiabetic agents, administered in combination, might be required to curb this menace and maintain normal blood glucose. To this end, natural compounds were screened to identify small molecular weight compounds with inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), dipeptidyl-peptidase-4 (DPP-4), and α-amylase. From the result, the top 5 anthocyanins with the highest binding affinity are reported herein. Further ADMET profiling showed moderate pharmacokinetic profiles for these compounds as well as insignificant toxicity. Cyanidin 3-(p-coumaroyl)-diglucoside-5-glucoside (−15.272 kcal/mol), cyanidin 3-O-(6ʺ-malonyl-3ʺ-glucosyl-glucoside) (−9.691 kcal/mol), and delphinidin 3,5-O-diglucoside (−12.36 kcal/mol) had the highest binding affinities to PTP1B, DPP-4, and α-amylase, respectively, and can be used in combination to control glucose fluctuations. However, validations must be carried out through further in vitro and in vivo tests.

Topoisomerase II alpha catalyses and guides the unknotting of DNA by creating double transient breaks in the DNA using a conserved tyrosine as the catalytic residue. Topoisomerase II alpha has been shown to be overexpressed in numerous types of cancers and it is a target for multiple chemotherapeutic agents. Many DNA topoisomerase inhibitors have been identified from natural sources and have been reviewed in many reports as anticancer agents. In the present study, a total of 240 phytochemicals characterized from four reported anticancer plants (Anacardium occidentale, Andrographis paniculata, Cannabis sativa and Tinospora cordifolia) were obtained from literatures and screened against the binding pocket of topoisomerase II alpha. From the pool of phytochemicals only 7-o-methylcyanidin, 20-betaecdysone, Andropanoside and Palmatoside-G qualified as Phyto-compounds with good oral bioactivity when subjected to the Lipinski’s rule of five. Bioassay data containing the IC50 of compounds screened against topoisomerase II alpha was used to generate a regression model using the 3D-QSAR techniques. A very viable model with R2 = 0.954, adjusted R2 = 0.908, Pearson R = 0.977, cross validation Q2 = 0.851, Standard Error of Estimate = 0.125, F = (20.803, p < 0.05) and Durbin-Watson constant = 1.613 was obtained. The 3D-QSAR result shows that Andropanoside and 20-betaecdysone may be better inhibitors of topoisomerase II alpha catalytic site than the standard drug, Etoposide. To further confirm this, the molecular interactions of Andropanoside and 20-betaecdysone were compared to those of Etoposide using the ligand interaction interface of Maestro environment.

Background: Chronic myelogenous leukaemia (CML) constitutes about 15% of adult leukaemia and is characterized by the overproduction of immature myeloid cells. Methods: In this study, a virtual high throughput screening (vHTS) technique was employed to screen a library of phytochemicals of reported anti-cancer plants. A docking score of -10 kcalmol­1 was used as the cut-off for the selection of phyto-compounds for pharmacophore-based virtual screening. Statistically robust and thoroughly validated QSAR model (R = 0.914, R2 = 0.836, Adjusted R2 = 0.764, LOO-CV= 0.6680) was derived for the inhibition of BCR-ABL kinase domain. Results: The virtual screening, pharmacophore screening, QSAR model and molecular docking techniques applied herein revealed ellagic acid, a polyphenolic compound, as a potential competitive inhibitor of the BCR-ABL kinase domain. Ellagic acid binds to the inactive ABL state and forms similar interactions with key residues within the BCR-ABL Kinase domain as obtained in ponatinib (possesses inhibitory effects on the ABL thr-315I mutant). It forms hydrogen bond interaction with thr-315 residue (the gatekeeper residue). It is not likely to be prone to the various mutations associated with nilotinib because of its small size. Conclusion: The procedure of VHTs, Pharmacophore, QSAR, and molecular docking applied in this study could help in detecting more anti-CML compounds.

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