Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists

Abstract

Farnesoid X receptor (FXR) is a potential therapeutic target for the treatment of diabetes mellitus. Atom-based three-dimensional quantitative structure activity relationship (3D-QSAR) models were developed for a series of 48 benzimidazole-based agonists of FXR. A total of five pharmacophore hypotheses were generated based on the survival score to build QSAR models. HHHRR was considered as a best model that consisted of three hydrophobic features (H) and two aromatic rings (R). The best hypothesis, HHHRR yielded a 3D-QSAR model with good statistical value (R(2)) of 0.8974 for a training set of 39 compounds and also showed good predictive power with correlation coefficient (Q(2)) of 0.7559 for a test set of nine compounds. Furthermore, molecular docking simulation was performed to understand the binding affinity of 48 benzimidazole-based compounds against the active site of human FXR protein. Docking results revealed that both the most active and least active compounds showed similar binding mode to the experimentally observed binding mode of co-crystallized ligand. The generated 3D contour maps revealed the structure activity relationship of the compounds. Substitution effects at different positions of benzimidazole derivatives would lead to the discovery of new agonists against human FXR protein.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity

“…In the regression model, R 2 was used to describe the fitness of data, the correlation coefficient ( Q 2 ) was used to check the external predictability, and the significance of the model was measured by the Fisher ratio ( F ) [ 31 , 36 , 37 ]. Thus, the best QSAR model was chosen based on maximum survival score, good statistical value, good predictive power, and lowest relative conformational energy.…”

“…Pharmacophore sites were produced based on the pharmacophore features in the Phase module. There are six built-in pharmacological features in Phase, namely, hydrogen bond receptor (A), hydrogen bond donor (D), hydrophobic group (H), negatively charged group (N), positively charged group (P), and aromatic ring (R) [ 31 ]. In the generated hypotheses, six common sites were found for all selected compounds.…”

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

“…Previous reports indicate that BA regulates energy expenditure in a FXR-independent manner in mice through the activation of TGR5 5,6 . Activation of FXR helps to treat liver fibrosis, diabetes, atherosclerosis, cholesterol gallstone disease, erectile dysfunction, obesity, metabolic syndrome and inflammatory bowel disease 7,8 .…”

“…5,6 The activation of FXR helps to treat liver fibrosis, diabetes, atherosclerosis, cholesterol gallstone disease, erectile dysfunction, obesity, metabolic syndrome and inflammatory bowel disease. 7,8 Takeda G-protein-coupled receptor-5 (TGR5) is a G-protein coupled receptor that plays a key role in energy and glucose homeostasis. The activation of TGR5 acts as a target for the treatment of obesity, diabetes and metabolic syndromes.…”