Structural Insights from Binding Poses of CCR2 and CCR5 with Clinically Important Antagonists: A Combined In Silico Study

Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å), we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2) and Glu283 (CCR5) are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design

Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease. © 2022 World Scientific Publishing Company

Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period

Background: Multiple sclerosis (MS) is a devastating autoimmune disorder characterized by oligodendrocytes (OLGs) loss and demyelination. In this study, we have examined the effects of metformin (MET) on the oligodendrogenesis, redox signaling, apoptosis, and glial responses during a self-repairing period (1-week) in the animal model of MS. Methods: For induction of demyelination, C57BL/6 J mice were fed a 0.2 cuprizone (CPZ) for 5 weeks. Thereafter, CPZ was removed for 1-week and molecular and behavioral changes were monitored in the presence or absence of MET (50 mg/kg body weight/day). Results: MET remarkably increased the localization of precursor OLGs (NG2+/O4+ cells) and subsequently the renewal of mature OLGs (MOG+ cells) in the corpus callosum via AMPK/mammalian target of rapamycin (mTOR) pathway. Moreover, we observed a significant elevation in the antioxidant responses, especially in mature OLGs (MOG+/nuclear factor erythroid 2-related factor 2 (Nrf2+) cells) after MET intervention. MET also reduced brain apoptosis markers and lessened motor dysfunction in the open-field test. While MET was unable to decrease active astrogliosis (GFAP mRNA), it reduced microgliosis by down-regulation of Mac-3 mRNA a marker of pro-inflammatory microglia/macrophages. Molecular modeling studies, likewise, confirmed that MET exerts its effects via direct interaction with AMPK. Conclusions: Altogether, our study reveals that MET effectively induces lesion reduction and elevated molecular processes that support myelin recovery via direct activation of AMPK and indirect regulation of AMPK/Nrf2/mTOR pathway in OLGs. These findings facilitate the development of new therapeutic strategies based on AMPK activation for MS in the near future. © 2019, Maj Institute of Pharmacology Polish Academy of Sciences

Evaluation of sesquiterpene coumarins from Ferula assa-foetida on VEGF, MMP9, MMP2 and study of biding modes using computational methods

Background and objectives: Ferula assafoetida of Apiaceae family bears sesquiterpene coumarins from phenolic class. Studies have shown that phenolic compounds at physiological concentration can inhibit two groups of gelatinase matrix metalloproteinases. So, the ability of compounds of this plant to inhibit the enzymes mentioned above seems to be useful. Methods: Acetone extract of plant was prepared and sesquiterpene coumarins were purified using column chromatography and HPLC preparative analyses and their structures were elucidated. After culturing the cell to proper confluence, the cells were isolated and the supernatant was removed. The pure substances were applied on cell lines U87MG and WEHI. In the computational part, the structure has been docked in the active site of metalloproteinase, and significant interactions were determined. Subsequently, ligand-protein complexes were subjected to molecular dynamics simulation in water and thermodynamic properties were calculated. Results: In the phytochemistry field galbanic acid, mogoltadone, kellerin, polyanthin and polyanthinin were extracted from F. assafoetida. Biological investigation demonstrated significant changes in the amount and activity of matrix metalloproteinase and vascular endothelial growth factor. Ligand binding to the active site of the protein was studied in computational causing conformational changes in the active site of the protein. Conclusion: Investigation revealed that the coumrins have inhibitory effects on the content and activity of MMP 2.9 and showed anti-angiogenetic effect. So, they can be potentially effective in the treatment of cancer. Interactive and competitive binding between MMP-9 and galbanic acid were studied with FT-IR, UV-Vis and fluorescence methods and MMP-9 structure was changed in these interactions