In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

Abstract

The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B (27) and microlobidene (28), were confirmed as GPBAR1 activators reaching more than 50% receptor activation at 20 μM with EC50s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin.

Preparation of a steroid-oxazole-1,2′-[1,3]oxazete] derivative: biological and theoretical evaluation of its interaction with a kinase protein (CK2)

“…The 3D pharmacophore model for the compounds 2, 3 and 4 was determinate using LigandScout 4.08 software [26].…”

“…This pharmacophore model can furnish a new insight to design novel molecules that can enhance or inhibit the function of the target and will be useful in drug discovery strategies. Therefore, in this study, LigandScout software [26] was used to develop a pharmacophore model of compounds 2-4. The results showed in the Fig.…”

“…(2) Electrostatic energy that is the product of electrical charge and electrostatic potential, which are involved in the ligand-protein system; 3) total intermolecular energy and (4) Van der Waals (vdW) + hydrogen bond (Hbond) + desolvation energy (Desolv. Energy; which have an influence on the movement of water molecules into or out of the ligand-protein system) using a theoretical model [26]. The results showed that there are differences in the thermodynamic parameters of compound 4 compared to quinalizarin; In addition, the inhibition constant (Ki) for compound 4 was lower than Ki for quinalizarin ( Table 5).…”

New chloroamide-steroid derivative with biological activity on a casein kinase 2 (CK2)

“…The 3D pharmacophore model for the compounds 2-4 was determinate using LigandScout 4.08 software [25]. Biological Method.…”

Preparation of two steroid derivatives and its theoretical interaction with a 17β‐hydroxysteroid dehydrogenase type 1

“…The 3D pharmacophore model for the compounds 2, 3 and 4 was determinate using LigandScout 4.08 software [17] Theoretical evaluation of the interaction between both compounds 2 and 3 with 17β-hydroxysteroid dehydrogenase type 1 (3HB4). The interaction of compound 4 with 1IOL [18] protein was carried out using the Docking Server software [19]; additionally, two 17β-HD types 1 inhibitors such as fisetin and methyl paraben [20,21] were used as controls.…”