Abstract Cathepsin K and S are two isoforms of cysteine protease with diverse biological functions in the aspect of osteoporosis and autoimmune diseases. Accordingly, the homologous sequence and similar binding site features among CTSK/S may lead to unselective inhibition and side effects. To address such issue, various computational strategies were applied in the current study to explore the selectivity mechanism of CTSK/S inhibitors, including sequence alignment, molecular docking, MD simulations, MM/GBSA energy calculation, and so on. Our findings highlight the notable effects of CTSK residues Glu59 and Tyr67, as well as CTSS residue Asn67 on inhibition selectivity. Overall, this study provides an informative guideline for the rational design of CTSK/S selective inhibitors.
The strategy of enlarging the molecular size, increasing hydrogen bond interactions with the key residues of CB2, and furthering geometric distribution of hydrophobic groups would improve the selectivity towards CB2 receptor.
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Background: The lipid bilayer of the plasma membrane is impermeable to ions, yet changes in the flux of ions across the cell membrane are critical regulatory events in cells. Because of their regulatory roles in a range of physiological processes, such as electrical signaling in muscles and neurons, to name a few, these proteins are one of the most important drug targets. Objective: This review mainly focused on the computational approaches for elucidating proteinprotein interactions in cation channel signaling. Discussion: Due to continuously advanced facilities and technologies in computer sciences, the physical contacts of macromolecules of channel structures have been virtually visualized. Indeed, techniques like protein-protein docking, homology modeling, and molecular dynamics simulation are valuable tools for predicting the protein complex and refining channels with unreleased structures. Undoubtedly, these approaches will greatly expand the cation channel signaling research, thereby speeding up structure-based drug design and discovery. Conclusion: We introduced a series of valuable computational tools for elucidating protein-protein interactions in cation channel signaling, including molecular graphics, protein-protein docking, homology modeling, and molecular dynamics simulation.
Psammaplin A (PsA) is a bromotyrosine disulfide dimer with histone deacetylase (HDAC) inhibition and acts through reduced monomer PsA-SH. We studied the connection of HDAC inhibition, cell growth inhibition, and apoptosis induction of PsA-SH by modifying the -SH group with deletion (6a) or replacement with hydroxamic acid (10b) or benzamide (12g). PsA-SH inhibits HDAC1/2/3 and 6a loses the HDAC inhibition ability. 10b inhibits HDAC1/2/3/6 while 12g shows selective inhibition of HDAC3. PsA-SH and 10b, but neither 6a nor 12g, induce apoptosis in human leukemia HL-60 cells associated with increased acetylation of Histone H3. PsA-SH and 10b inhibit growth of several solid tumor cell lines in vitro and Lewis lung cancer cell growth in vivo. PsA-SH is a simple scaffold for developing selective HDAC inhibitors and induces apoptosis through inhibiting HDAC1/2.
Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro . CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.
5-hydroxytryptamine 2A (5-HT2A) receptor is emerging as an important target for numerous psychoactive drugs due to its imperative roles in psychological diseases. In fact, multiple 5-HT2A receptor antagonists were developed to treat numerous psychiatric disorders, however, their clinical outcome was far from ideal probably due to a blurry information of the exact interaction modes between the receptor and its antagonists. Impressively, with a recent release of its crystal structure, we carefully analyzed the receptor-ligand interactions with Protein Contacts Atlas, structure-based pharmacophore models, and molecular dynamics (MD) simulations to sum up the chemical features for antagonists interacting with 5-HT2A receptor. Moreover, the molecular docking-based virtual screening was applied to discover potential 5-HT2A receptor antagonists from FDA and TCMNP databases. Intriguingly, after a systematic assessment of the docking scores, binding modes and free energies, as well as their MD simulations performances, three compounds in TCMNP database were highlighted to be potential 5-HT2A receptor antagonists. Fascinatedly, these three hits also exhibited highly binding affinities with dopamine D2 receptor (D2R) due to the similarity of the ligand binding pockets of the receptors, indicating them to be promising dual target molecules that are of great benefit for anti-psychotic-drug research and development. In addition, ADME/Tox predictions were conducted for a primary evaluation of their developing potential. Together, this study not only revealed the exact interaction modes between 5-HT2A receptor and its antagonists, which shed a light on a better access for developing its novel antagonists, but also provided promising dual D2 and 5-HT2A receptor antagonists.Communicated by Ramaswamy H. Sarma
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