According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.

Since its isolation in 1818, strychnine has attracted the attention of chemists and pharmacologists. Here, we discuss structures, syntheses, metabolic transformations, and pharmacological actions of the alkaloid and its mono- and dimeric analogues.

C-C chemokine receptor type 5 (CCR5) is a member of the G protein-coupled receptor. CCR5 and its interaction with chemokine ligands have been crucial for understanding and tackling human immunodeficiency virus (HIV)-1 entry into target cells. In recent years, the change in CCR5 expression has been related to the progression of different cancer types. Patients treated with the CCR5 ligand, maraviroc (MVC), showed a deceleration in tumor development especially for metastatic colorectal cancer. Based on the crystal structure of CCR5, we herein describe a multistage virtual screening protocol including pharmacophore screening, molecular docking, and protein–ligand interaction fingerprint (PLIF) postdocking filtration for discovery of novel CCR5 ligands. The applied virtual screening protocol led to the identification of four hits with binding modes showing access to the major and minor pockets of the MVC binding site. Compounds 2–4 showed a decrease in cellular proliferation upon testing on the metastatic colorectal cancer cell line, SW620, displaying 12, 16, and 4 times higher potency compared to MVC, respectively. Compound 3 induced apoptosis by arresting cells in the G0/G1 phase of the cell cycle similar to MVC. Further in vitro assays showed compound 3 drastically decreasing the CCR5 expression and cellular migration 48 h post treatment, indicating its ability to inhibit metastatic activity in SW620 cells. The discovered hits represent potential leads for the development of novel classes of anticolorectal cancer agents targeting CCR5.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Repurposing of approved pharmaceutical drugs for COVID-19 treatment represents an attractive approach to quickly identify promising drug candidates. SARS-CoV-2 main protease (M^pro) is responsible for the maturation of viral functional proteins making it a key antiviral target. Based on the recently revealed crystal structures of SARS-CoV-2 M^pro, we herein describe a multi-stage virtual screening protocol including pharmacophore screening, molecular docking and protein-ligand interaction fingerprints (PLIF) post-docking filtration for efficient enrichment of potent SARS-CoV-2 M^pro inhibitors. Potential hits, along with a cocrystallized control were further studied via molecular dynamics. A 150-ns production trajectory was followed by RMSD, free energy calculation, and H-bond analysis for each compound. The applied virtual screening protocol led to identification of five FDA-approved drugs with promising binding modes to key subsites of the substrate-binding pocket of SARS-CoV-2 M^pro. The identified compounds belong to different pharmaceutical classes, including several protease inhibitors, antineoplastic agents and a natural flavonoid. The drug candidates discovered in this study present a potential extension of the recently reported SARS-CoV-2 M^pro inhibitors that have been identified using other virtual screening protocols and may be repurposed for COVID-19 treatment.

Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of small-molecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.