Increased toll-like receptor-2 expression on nonclassic CD16⁺monocytes from patients with inflammatory stage of eales' disease

Purpose.: To identify the distribution, differential Toll-like receptor (TLR) expression, and functional contribution of monocyte subpopulations in the inflammatory stage of Eales' disease (ED). Methods.: Peripheral blood mononuclear cells were isolated from nine patients during the inflammatory stage of ED and nine age- and sex-matched healthy controls. The expression of CD14, CD16, TLR-2, and TLR-4 on monocytes was measured by flow cytometry. The CD14+, CD16−, and CD16+ monocyte populations were sorted on the basis of magnetic-activated cell-sorting methodology, and levels of cytokines were measured by ELISA. Results.: In ED patients, the number of circulating monocytes was significantly expanded compared with that in controls (P = 0.01), with a marked increase in the nonclassic CD16+ subset, which showed an activated phenotype in patients that correlated with levels of serum proinflammatory cytokines and clinical progression. A higher expression of cell surface TLR-2 (P = 0.02), but not TLR-4, was found in monocytes of patients with ED. Furthermore, TLR-2 was expressed at higher levels on CD16+ monocytes than on CD16− monocytes in patients, whereas no significant variation was found in TLR-4 expression on different monocyte subsets. Peptidoglycan-induced TNF-α expression correlated with TLR-2 expression in monocytes isolated from controls (r = 0.85, P = 0.0061), but not in monocytes isolated from ED patients (r = 0.553, P = 0.1328). Conclusions.: These results indicate that in the pathogenesis of ED, TLR activation and increased numbers of nonclassic CD16+ monocytes are crucial regulators, along with the secretion of proinflammatory cytokines that perpetuate the inflammatory process in the retina

Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent

Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r 2 = 0.972, SD = 0.3, F = 173.4, Q 2 = 0.712, RMSE = 0.3, Person-R = 0.94, and r 2 pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research

Hybrid Computational Simulation and Modeling Assisted Structural Analysis of Anti-tubercular Molecules

AbstractTuberculosis (TB), a leading cause of death worldwide, in association with HIV-AIDS and the emergence of multi-drug resistance (MDR) or extensively drug resistance (XDR) strains, has created necessity to develop new class of anti-tubercular drug. Strategic implementation of hybrid computational simulation and searching method has been used to analyze and explore new chemical entity effective against MDR Tuberculosis strains. Initially a ligand-based pharmacophore hypothesis and 3D Quantitative structure activity relationship (QSAR) model with statistical significance (R2=0.985, SD=0.146, Pearson R=0.936, Q2= 0.849, R2Pred=0.851, Q2(F2)=0.854) was generated by well validated algorithm. Concurrently molecular docking analysis was performed by considering three individual grid points of InhA enzyme. Moreover Ligand-based pharmacophoric model was drastically re-assessed against receptor-based docking simulation model to authenticate this in silico trialing. The docking analysis indicates that this class of ligands nicely occupies the hydrophobic pocket of InhA enzyme, which is an important feature of direct InhA inhibitors and it reveals that the chemical entities can inhibit the aforementioned enzyme without activating katG (a catalase/peroxidase enzyme) enzyme pathway

Synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine

A series of 2-substituted and 2,3-substituted quinazolin -4(3H)-one derivatives were designed and synthesized based on the structure of febrifugine. The structures of the new compounds were confirmed by spectral analysis. The in vivo biological activity test results indicated that those compounds exhibited antimalarial activities against Plasmodium berghei in mice, at a dose of 5 mg/kg. Compared to Chloroquine and Artemisinin, these compounds have the advantages of shorter synthetic routes and consequently are highly cost effective in nature

Structure-based drug design-guided identification of estrogen receptor binders

Cancer is one of the life-threatening diseases and the second leading cause of death in the world. The estrogen receptor can be considered as one of the significant drug targets for cancer. A large number of clinically used anticancer drugs were identified from phytochemicals. Multiple literatures suggested that extracts of Datura sp. significantly inhibit estrogen receptors associated with human cancer. In the present study, all reported natural products present in Datura sp. were subjected to molecular docking against estrogen receptors. The top hits were shortlisted based on binding orientation and docking score and subjected to molecular dynamics simulation to explore the conformational stability followed by binding energy calculation. The ligand [(1S,5R)-8-Methyl-8-Azabicyclo [3.2.1] Octan-3-yl] (2R)-3-Hydroxy-2-Phenylpropanoate depicts highly acceptable MD simulations outcomes and drug-likeness profile. Knowledge-based de novo design and similar ligand screening were executed using the structural information. The designed ligand DL-50 exhibited satisfactory binding, drug-likeness profile, and well-accepted ADMET profile followed by easy synthetic accessibility which further requires experimental validation. Graphical abstract: [Figure not available: see fulltext.]