Discovery of a Novel HIV-1 Integrase/p75 Interacting Inhibitor by Docking Screening, Biochemical Assay, and in Vitro Studies.

Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment.

Herbalog: A tool for target-based identification of herbal drug efficacy through molecular docking.

BACKGROUND: Traditionally, molecular docking is primarily employed to screen pure compounds; the top-ranking chemicals are subsequently selected for experimental validation. Unlike synthetic chemicals, most natural products are commercially unavailable. The isolation and purification of each natural product is extremely time-consuming, which has restricted the screening of lead compounds from natural products. PURPOSE: We developed a protocol, Herbalog, to facilitate the identification of bioactive phytochemicals through molecular docking. METHODS: We wrote a script using Python and Autodock Vina for docking; ligand displacement and adipolysis assays were used to determine the anti-fatty acid binding protein (FABP) 4 activity of bioactive extracts. An ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry system was applied for identifying major peaks of bioactive extracts. RESULTS: Herbalog, a natural product database, contains 5,112 phytochemicals from 197 common herbs and a script that counts the number of hits from docking in each herb and calculates the hit rate of herbs. Herbalog prioritizes herbs according to their hit rates, and top-ranking herb candidates contain a large repertoire of hits. We used Herbalog as a screening tool and identified labdane diterpenoids from Andrographis paniculata as leading candidates of FABP4 inhibitors. CONCLUSION: Herbalog facilitates the discovery of herbs that possess the highest number of inhibitors or activators against target proteins, which reduces the sample preparation time for preliminary validation.

Silibinin, a novel chemokine receptor type 4 antagonist, inhibits chemokine ligand 12-induced migration in breast cancer cells.

PURPOSE: C-X-C chemokine receptor type 4 (CXCR4) signaling has been demonstrated to be involved in cancer invasion and migration; therefore, CXCR4 antagonist can serve as an anti-cancer drug by preventing tumor metastasis. This study aimed to identify the CXCR4 antagonists that could reduce and/or inhibit tumor metastasis from natural products. METHODS AND RESULTS: According to the molecular docking screening, we reported here silibinin as a novel CXCR4 antagonist. Biochemical characterization showed that silibinin blocked chemokine ligand 12 (CXCL12)-induced CXCR4 internalization by competitive binding to CXCR4, therefore inhibiting downstream intracellular signaling. In human breast cancer cells MDA-MB-231, which expresses high levels of CXCR4, inhibition of CXCL12-induced chemomigration can be found under silibinin treatment. Overexpression of CXCL12 sensitized MDA-MB-231 cells to the inhibition of silibinin, which was abolished by CXCR4 knockdown. The inhibition of silibinin was also observed in MCF-7/CXCR4 cells rather than MCF-7 cells that express low level of CXCR4. CONCLUSIONS: Our work demonstrated that silibinin is a novel CXCR4 antagonist that may have potential therapeutic use for prevention of tumor metastasis.