Echinacoside is a natural compound with potent reactive oxygen species (ROS)-scavenging and anti-oxidative bioactivities, which protect cells from oxidative damages. As cancer cells are often under intense oxidative stress, we therefore tested if Echinacoside treatment would promote cancer development. Surprisingly, we found that Echinacoside significantly inhibited the growth and proliferation of a panel of cancer cell lines. Treatment of the human SW480 cancer cells with Echinacoside resulted in marked apoptosis and cell cycle arrest, together with a significant increase in active caspase 3 and cleaved PARP, and upregulation of the G1/S-CDK blocker CDKN1B (p21). Interestingly, immunocytochemistry examination of drug-treated cancer cells revealed that Echinacoside caused a significant increase of intracellular oxidized guanine, 8-oxoG, and dramatic upregulation of the double-strand DNA break (DSB)-binding protein 53BP1, suggesting that Echinacoside induced cell cycle arrest and apoptosis in SW480 cancer cells via induction of oxidative DNA damages. These results establish Echinacoside as a novel chemical scaffold for development of anticancer drugs.

Influenza A is an acute respiratory infectious disease caused by the influenza A virus, which seriously threatens global human health and causes substantial economic losses every year. With the emergence of new viral strains, anti-influenza drugs remain the most effective treatment for influenza A. Research on traditional, innovative small-molecule drugs faces many challenges, while computer-aided drug design (CADD) offers opportunities for the rapid and effective development of innovative drugs. This literature review describes the general process of CADD, the viral proteins that play an essential role in the life cycle of the influenza A virus and can be used as therapeutic targets for anti-influenza drugs, and examples of drug screening of viral target proteins by applying the CADD approach. Finally, the main limitations of current CADD strategies in anti-influenza drug discovery and the field’s future directions are discussed.

The influenza A virus polymerase acidic (PA) endonuclease is an attractive target for anti-influenza drug development. In this study, plant extracts were used to screen the inhibitor against the PA endonuclease and its mutant. In 45 kinds of plant extracts, eight can effectively inhibit the PA_N and PA_N–I38T mutant in the primary screening. Dose-dependent inhibition assay showed that Epimedii folium can effectivity inhibit the PA_N and PA_N–I38T with IC₅₀ of 11.23 and 26.03 μM, respectively. Furthermore, 130 ingredients of E. folium were virtually screened using the in silico method, and the compounds ginkgetin and bilobetin bind to the active pocket of PA_N and PA_N–I38T with a strong interaction force. Gel-based PA endonuclease analysis and inhibition type analysis identified that bilobetin can competitively inhibit the PA. Hence, bilobetin, as an ingredient of E. folium, was screened through in vitro and in silico research.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which plays a crucial role in the nuclear factor-kappa B (NF-κB) activation signaling pathway as a paracaspase, is a new target for immunomodulatory and antitumor drugs. Here, novel inhibitors that target MALT1 allosteric sites were identified by virtual screening FDA-approved drug databases. Paliperidone, a compound that binds to the allosteric site of MALT1, is investigated. An in vitro study found that the proteolytic activity of MALT1 substrate cleavage was blocked by paliperidone. Meanwhile, the MALT1 proteolytic activity was reversible, as demonstrated by the partial recovery of the MALT1 substrate cleavage following compound wash out. The docking analysis of the interaction of MALT1 and paliperidone suggested that two hydrogen bonds formed in the allosteric pocket of MALT1. MALT1 and paliperidone achieved a good equilibrium, as demonstrated by 100 ns molecular dynamic (MD) simulations conducted with the program Gromacs. However, the catalytically active site of the MALT1 complex with paliperidone remained in an inactive conformation. Thus, paliperidone, a noncompetitive and allosteric inhibitor, was screened through in silico and in vitro methods. This study will be of significance for the development of effective and selective drugs that can treat MALT1-driven cancer or autoimmune diseases.

COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.