Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction.

The immune checkpoint proteins are those key to the body's immunity which can either boost the immune system to protect the body from pathogens; or suppress the body's immunity system for the goal of self-tolerance. Cancer cells have evolved some mechanisms to boost the immuno-inhibitory checkpoints to bypass the immune system of the body. The binding of Programmed Cell Death-1 (PD-1) protein with its ligand Programmed Cell Death Ligand-1 (PD-L1) promotes this kind of immune-inhibitory signal. The discovery of immune checkpoint inhibitors was started in the early 21st century; with some success through monoclonal antibodies, peptides, and small molecules. Being the most reliable and safest way to target immune checkpoints, the scientific community is exploring possibilities to develop small molecule inhibitors. Among the different scaffolds of the small molecule, the most exposed and researched core molecule is Biphenyl-based scaffolds. We have described all of the possible biphenyl-based small molecules in this article, as well as their interactions with various amino acids in the binding cavity. The link between the in silico, in vitro, and in vivo activities of the PD-1/PD-L1 inhibitors are well connected. The Tyr56, Met115, Ala121, and Asp122 were detected as the crucial amino acids of the PD-1/PD-L1 inhibition. Additionally, a detailed binding pocket analysis of the PD-L1 receptor was carried out, where it was observed and confirmed that the binding pocket is tunnel-shaped and hydrophobic in nature. Finally, the structure-activity relationship of the biphenyl-based small molecule inhibitors was developed based on their activity and the binding interactions.

WITHDRAWN: Design and Discovery of Lophine Derivatives as Multitargeting Agents by Molecular Docking, ADMET, MD Simulation and Pharmacophore Analysis: A Computational Approach

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Computational analysis of natural product B-Raf inhibitors.

B-Raf protein is a serine-threonine kinase and an important signal transduction molecule of the MAPK signaling pathway that mediates signals from RAS to MEK, ultimately promoting various essential cellular functions. The B-Raf kinase domain is divided into two subdomains: a small N-terminal lobe and a large C-terminal lobe, with a deep catalytic cleft between them. The N-terminal lobe contains a phosphate-binding loop (P-loop) and nucleotide-binding pocket, while the C-terminal lobe binds the protein substrates and contains the catalytic loop. The ligand pharmacophore was generated by using 17 different natural products and the receptor pharmacophore was generated by using protein structures. The reported natural product B-Raf inhibitors were analyzed according to the pharmacophore analysis (HipHop fit), virtual screening tools by Lipinski's rule of five. Thirteen out of seventeen molecules share the best ligand based pharmacophoric model (HipHop_5). The best receptor based pharmacophoric model came as AADHR. The compounds were docked against the B-Raf receptors (PDB ID: 3OG7, 4XV2, 5C9C). The compound DHSilB with cDOCKER interaction energy of -62.7 kcal/mol, -83.3 kcal/mol, -73.6 kcal/mol as well as the compound DHSilA with cDOCKER interaction energy of -63.9 kcal/mol, -63.2 kcal/mol, -74.7 kcal/mol showed satisfactory interaction with the respective receptors. Finally, the MD simulation was run for 100 ns for the top docked compounds DHSilA and DHSilB with the B-Raf proteins (PDB ID: 3OG7, 4XV2 and 5C9C). After the MD simulation run for 100 ns, the ligand 2,3-dehydrosilybin A (DHSilA) was found to be more stable in terms of the trajectories of RMSD, RMSF, Rg and H-bonds.