Citrus nutraceutical eriocitrin and its metabolites are partial agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a molecular docking and molecular dynamics study.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are potent insulin sensitizers in treating type 2 diabetes. Despite being very effective in the fight against diabetes-mediated complications, PPARγ agonists are accompanied by severe side effects leading to complicated health problems, making the discovery of novel safe ligands highly pertinent. A significant intense research effort is in progress to explore the PPARγ activating potential of a wide range of natural compounds. Lemon (Citrus limon) contains various bioactive flavonoids, and eriocitrin is the major flavonoid. It possesses substantial antioxidant and anticancer, lipid-lowering activities and prevents obesity-associated metabolic diseases. Eriocitrin is metabolized to eriodictyol in the intestine, and the absorbed eriodictyol undergoes conversion to numerous metabolites in vivo. It is unclear if eriocitrin or its metabolites are responsible for their beneficial effects. We have used molecular docking, ADMET properties, drug-likeness score and molecular dynamics simulation study to find if eriocitrin and its metabolites are potent binders for PPARγ. Docking studies revealed that eriocitrin binds to PPARγ with the highest binding energy, but ADMET properties and in vivo studies show that the bioavailability of eriocitrin is very poor. Molecular dynamics studies were carried out to validate the docking results, and multiple parameters like RMSD, RMSF, Radius of gyration, SASA, hydrogen bond analysis, interaction energy, principal component analysis, Gibbs free energy and MM-PBSA were calculated. Based on our studies, eriodictyol, eriodictyol 7-O-glucuronide, eriodictyol 3'-O-glucuronide, homoeriodictyol and homoeriodictyol 7-O-glucuronide which are metabolites of eriocitrin appear to be potent partial agonists of PPARγ under physiological conditions.Communicated by Ramaswamy H. Sarma.

Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers.

While orthosteric ligands of the angiotensin II (AngII) type 1 receptor (AT1R) are available for clinical and research applications, allosteric ligands are not known for this important G protein-coupled receptor (GPCR). Allosteric ligands are useful tools to modulate receptor pharmacology and subtype selectivity. Here, we report AT1R allosteric ligands for a potential application to block autoimmune antibodies. The epitope of autoantibodies for AT1R is outside the orthosteric pocket in the extracellular loop 2. A molecular dynamics simulation study of AT1R structure reveals the presence of a druggable allosteric pocket encompassing the autoantibody epitope. Small molecule binders were then identified for this pocket using structure-based high-throughput virtual screening. The top 18 hits obtained inhibited the binding of antibody to AT1R and modulated agonist-induced calcium response of AT1R. Two compounds out of 18 studied in detail exerted a negative allosteric modulator effect on the functions of the natural agonist AngII. They blocked antibody-enhanced calcium response and reactive oxygen species production in vascular smooth muscle cells as well as AngII-induced constriction of blood vessels, demonstrating their efficacy in vivo. Our study thus demonstrates the feasibility of discovering inhibitors of the disease-causing autoantibodies for GPCRs. Specifically, for AT1R, we anticipate development of more potent allosteric drug candidates for intervention in autoimmune maladies such as preeclampsia, bilateral adrenal hyperplasia, and the rejection of organ transplants.

Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3ß.

Casein kinase 2 (CK2) and glycogen synthase kinase-3beta (GSK3ß) are responsible for the phosphorylation of a tumor suppressor protein (PTEN) in a cooperative manner which causes its deactivation. Thus, it is essential to inhibit both kinases simultaneously to prevent PTEN deactivation more efficiently. In this study, we have designed a novel lead from Hit15 which was identified in silico as a dual kinase inhibitor against CK2 and GSK3ß through our previous study. The dataset of structural analogs of the lead was designed and confirmed by pharmacophore mapping and molecular docking. The screened analogs were considered further and a series of "tetrahydrobenzo[d]thiazoles" were synthesized. Compound 1g has shown highest dual kinase inhibitory activity at a concentration of 1.9 µM against CK2 and 0.67 µM against GSK3ß. Our results suggest that the presence of a carboxyl group at the meta position of the phenyl ring plays a vital role in dual kinase inhibition.

Identification of dual kinase inhibitors of CK2 and GSK3ß: combined qualitative and quantitative pharmacophore modeling approach.

PTEN, a tumor suppressor protein, gets deactivated by casein kinase 2 (CK2) and glycogen synthase kinase 3ß (GSK3ß), which are the major causes of PI3K/AKT-driven tumors. To surmount this problem, the multi-target inhibitor strategy may be of great significance. The goal of this study was to design dual-target inhibitors of CK2 and GSK3ß using a combination of pharmacophore modeling and molecular docking studies. The common feature-based (qualitative) and 3DQSAR-based (quantitative) pharmacophore models were generated and validated. The best pharmacophore models (Pharm18 and Hypo1) comprised two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic features. The models were used to screen various chemical database and top mapped compounds from each database were selected. They were processed for Lipinski filter, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis, and docking studies. We have obtained six hits with comparable dock score to the reported inhibitors. We have concluded Hit15 as a competent candidate based on its docking and Density Functional Theory (DFT) calculations. It showed 140.73 and 130.79 dock score in CK2 and GSK3ß, respectively. The electronic property of Hit 15 showed the lowest energy gap (0.021) compared to other hits and active ligands which suggest its higher reactivity. In conclusion, this study may assist in the development of new potent dual kinase inhibitors of CK2 and GSK3ß. Also, the overture effort of combined qualitative and quantitative modeling for the development of multi-target inhibitors may support the future endeavors.