Computer-aided screening for suppressor of variegation 4-20 homolog 1 inhibitors and their preliminary activity validation in human osteosarcoma.

Histone methylation/demethylation facilitate to maintain balanced histone methylation levels and underpin gene regulation, playing the key roles in epigenetic regulation. Suppressor of variegation 4-20 homolog 1 (SUV420H1), a member of class Histone Lysine Methyltransferase and a key enzyme in the epigenetic regulation of the pathways controlling metabolism and tumorigenesis, is crucial to maintain cell homeostasis. The inhibition of SUV420H1 has emerged as a promising candidate for drug development and cancer therapy. Herein, two potential and potent SUV420H1 inhibitors (ZINC08398384, ZINC08439608) were identified through in silico approach and in vitro biological experiments. In vitro biological tests demonstrated that these compounds can inhibit the proliferation of U2OS cells and restrict its migration ability. And the level of dimethylation of lysine 20 on histone H4 (H4K20me2) was markedly decreased by these compounds-treatment in a dose-dependent manner. These results indicated that ZINC08398384 and ZINC08439608 are potential SUV420H1 inhibitors and could be developed as promising drug candidates applied to cancer epigenetic therapy.Communicated by Ramaswamy H. Sarma.

A novel mannose-binding lectin from Liparis nervosa with anti-fungal and anti-tumor activities.

Plant lectins are carbohydrate-binding proteins with nonimmune origin, which can reversibly bind with carbohydrates, agglutinate cells, and precipitate polysaccharides and glycoconjugates. Plant lectins have attracted much attention for their anti-virus, anti-proliferation, and pro-apoptosis properties. Thus the exploration of new lectins has received special attention. Here we purified a mannose-binding lectin from the rhizomes of Liparis nervosa by ion exchange chromatography on DEAE-Sepharose, affinity chromatography on Mannose-Sepharose 4B, and gel filtration chromatography on Sephacryl S-100. The purified L. nervosa lectin (LNL) was identified to be a monomeric protein with a molecular mass of 13 kDa. LNL exhibited hemagglutinating activity towards rabbit erythrocytes, and its activity could be strongly inhibited by D-mannose, N-acetyl glucosamine and thyroglobulin. In vitro experiments showed that LNL exhibited a comparable anti-fungal activity against Piricularia oryzae (Cavara), Bipolaris maydis, Fusarium graminearum, and Sclerotium rolfsii, and anti-proliferation activity against tumor cells by inducing apoptosis. The full-length cDNA sequence of LNL is 715 bp in length and contains a 525 bp open reading frame (ORF) encoding a 110-residue mature protein. It was predicted to have three mannose-binding conserved motifs 'QXDXNXVXY'. The binding pattern of LNL was further revealed by homology modeling and molecular docking. We demonstrated that LNL is not only a potential therapeutic candidate against tumor but also a new anti-fungal agent.

Identification potential inhibitors against the Streptococcus quorum-sensing signal pathway.

Streptococcal infections are common in human and antibiotics are frequently prescribed in clinical practice. However, infections caused by drug-resistant strains are particularly difficult to treat using common antibiotics. Hence, there is an urgent need for new antibiotics. Quorum sensing is a regulatory mechanism involving cell communication that is thought to play an important role in various bacterial infections, including those caused by Streptococcus. The ATP-binding cassette transporter ComA of Streptococcus is essential for quorum-sensing signal production. The inhibition of the ComA peptidase domain (ComA PEP) suppresses the quorum-sensing pathway and resulting changes in phenotype and/or behavior. Using virtual screening and molecular dynamics simulations, two promising candidate compounds, ZINC32918029 and ZINC6751571, were found. These compounds had similar binding modes and interactions to the experimentally determined reference inhibitor 6CH. However, a significantly stronger negative binding energy was achieved (-113.501 ± 15.312 KJ/mol and -103.153 ± 11.912 KJ/mol for ZINC32918029 and ZINC6751571, respectively). Molecular dynamics simulations also revealed that ZINC32918029 and ZINC6751571 had a strong affinity for ComA PEP. These results indicate that ZINC32918029 and ZINC6751571 are promising candidate inhibitors of the Streptococcus quorum-sensing pathway.Communicated by Ramaswamy H. Sarma.