AIM OF THE STUDY: This study explores the anti-inflammatory effect of TPTQ in silico, in vitro, and in vivo.
MATERIALS AND METHODS: In silico testing used the Gnina application, opened via Google Colab. The TPTQ structure was docked with the nuclear factor kappa B (NF-ĸB) protein (PDB: 2RAM). In vitro testing began with testing the cytotoxicity of TPTQ against Raw 264.7 cells, using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) method. A phagocytic activity test was carried out using the neutral red uptake method, and interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretion tests were carried out using the enzyme-linked immunosorbent assay (ELISA) method. In vivo, tests were carried out on mice by determining cluster of differentiation 8+ (CD8+), natural killer cell (NK cell), and IL-6 parameters, using the ELISA method.
RESULTS: TPTQ has a lower binding energy than the native ligand and occupies the same active site as the native ligand. TPTQ decreased the phagocytosis index and secretion of IL-6 and TNF-α experimentally in vitro. TPTQ showed significant downregulation of CD8+ and slightly decreased NK cells and IL-6 secretion in vivo.
CONCLUSION: The potent inhibitory effect of TPTQ on the immune response suggests that TPTQ can be developed as an anti-inflammatory agent, especially in the treatment of Covid-19.
RESULTS: The Condorcet fusion method was examined. This approach combines the outputs of similarity searches from eleven association and distance similarity coefficients, and then the winner measure for each class of molecules, based on Condorcet fusion, was chosen to be the best method of searching. The recall of retrieved active molecules at top 5% and significant test are used to evaluate our proposed method. The MDL drug data report (MDDR), maximum unbiased validation (MUV) and Directory of Useful Decoys (DUD) data sets were used for experiments and were represented by 2D fingerprints.
CONCLUSIONS: Simulated virtual screening experiments with the standard two data sets show that the use of Condorcet fusion provides a very simple way of improving the ligand-based virtual screening, especially when the active molecules being sought have a lowest degree of structural heterogeneity. However, the effectiveness of the Condorcet fusion was increased slightly when structural sets of high diversity activities were being sought.