Network pharmacology of bioactives from Sorghum bicolor with targets related to diabetes mellitus.

BACKGROUND: Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. METHODS: Compounds in SB were explored through GC-MS and screened by Lipinski's rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. RESULTS: GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski's rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-ß-sitosterol, PPARD-ß-sitosterol, and PPARG-ß-sitosterol). CONCLUSION: Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.

Identification of Fatty Acid Binding Protein 5 Inhibitors Through Similarity-Based Screening.

Fatty acid binding protein 5 (FABP5) is a promising target for development of inhibitors to help control pain and inflammation. In this work, computer-based docking (DOCK6 program) was employed to screen ∼2 M commercially available compounds to FABP5 based on an X-ray structure complexed with the small molecule inhibitor SBFI-26 previously identified by our group (also through virtual screening). The goal was discovery of additional chemotypes. The screen resulted in the purchase of 78 candidates, which led to the identification of a new inhibitor scaffold (STK-0) with micromolar affinity and apparent selectivity for FABP5 over FABP3. A second similarity-based screen resulted in three additional hits (STK-15, STK-21, STK-22) from which preliminary SAR could be derived. Notably, STK-15 showed comparable activity to the SBFI-26 reference under the same assay conditions (1.40 vs 0.86 µM). Additional molecular dynamics simulations, free energy calculations, and structural analysis (starting from DOCK-generated poses) revealed that R enantiomers (dihydropyrrole scaffold) of STK-15 and STK-22 have a more optimal composition of functional groups to facilitate additional H-bonds with Arg109 of FABP5. This observation suggests enantiomerically pure compounds could show enhanced activity. Overall, our study highlights the utility of using similarity-based screening methods to discover new inhibitor chemotypes, and the identified FABP5 hits provide a strong starting point for future efforts geared to improve activity.