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Toxoplasma gondii (T. gondii) is one of the most successful parasites in the world, because about a third of the world's population is seropositive for toxoplasmosis. Treatment regimens for toxoplasmosis have remained unchanged for the past 20 years, and no new drugs have been introduced to the market recently. This study, performed molecular docking to identify interactions of FDA-approved drugs with essential residues in the active site of proteins of T. gondii Dihydrofolate Reductase (TgDHFR), Prolyl-tRNA Synthetase (TgPRS), and Calcium-Dependent Protein Kinase 1 (TgCDPK1). Each protein was docked with 2100 FDA-approved drugs using AutoDock Vina. Also, the Pharmit software was used to generate pharmacophore models based on the TgDHFR complexed with TRC-2533, TgPRS in complex with halofuginone, and TgCDPK1 in complex with a bumped kinase inhibitor, RM-1–132. Molecular dynamics (MD) simulation was also performed for 100 ns to verify the stability of interaction in drug–protein complexes. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis evaluated the binding energy of selected complexes. Ezetimibe, Raloxifene, Sulfasalazine, Triamterene, and Zafirlukast drugs against the TgDHFR protein, Cromolyn, Cefexim, and Lactulose drugs against the TgPRS protein, and Pentaprazole, Betamethasone, and Bromocriptine drugs against TgCDPK1 protein showed the best results. These drugs had the lowest energy-based docking scores and also stable interactions based on MD analyses with TgDHFR, TgPRS, and TgCDPK1 drug targets that can be introduced as possible drugs for laboratory investigations to treat T. gondii parasite infection. [ABSTRACT FROM AUTHOR]

Today, fungal infection has become more common disease especially in some cases, such as AIDS, cancer, and organ transplant which the immune system is suppressed. On the other hand, due to the increasing resistance to current antifungal drugs, more and more options for design of novel more efficient compounds with higher resistance are needed. In this study, a series of a fluconazole analogues were subjected to quantitative structure-activity relationship analysis to find the structure requirements for modeling adequate candidate. The best multiple linear regression equation was achieved from GA-PLS and MLR modeling. Subsequently, in silico screening study was applied to found new potent lead compounds based on the resulted model. The ability of the best designed compounds for antifungal activity was investigated by using molecular dynamic (MD) and molecular docking simulation. The results showed that compound F13 can efficiently bind to lanestrol 14-α demethylase target similar to other antifungal azoles. The molecular docking studies revealed an interesting binding profile with very high receptor affinity to the CYP51 active site. The triazole moiety of ligand F13 pointed to HEM group in lanestrol 14-α demethylase site and coordinated to Fe of HEM through its N4 atom. Also, there was a convenient relevance between QSAR and docking results. With the compound F13 which demonstrated the most promising minimum inhibitory concentration (MIC) values, it can be concluded that F13 is appropriate candidate for the development as antifungal agent. [ABSTRACT FROM AUTHOR]

In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)− 4 H-benzo[ b ] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6–311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in -vivo performance. [Display omitted] • 1,4 benzothiazine 3-one derivatives were synthesized as anticonvulsant agents. • The benzothiazine containing 4-bromo-benzyl substitution, increased the latency of convulsions. • The computational studies and biology assay indicated that compound 4h might had a good inhibitory effect on GABA-A receptor. • The results of the computational study and experimental methods about compound 4h were agreement together. [ABSTRACT FROM AUTHOR]

Design, synthesis, in vitro, and in silico enzymatic evaluations of thieno[2,3- b ]quinoline-hydrazones as novel inhibitors for α-glucosidase. [Display omitted] • Quinoline, thiophene, and hydrazone were selected as the potent pharmacophores against α-glucosidase. • Thieno[2,3- b ]quinoline-hydrazones 9 were synthesized as the new α-glucosidase inhibitors. • Compounds 9c-d , 9h , and 9l exhibited high anti-α-glucosidase activity. • Compounds 9c was a promising lead in order to achieve an anti-diabetes drug. In the development of novel anti-α-glucosidase agents, we synthesized novel thieno[2,3- b ]quinoline-hydrazones 9a-n by facile and efficient conventional chemical reactions. These compounds were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Inhibitory activities of the title compounds were evaluated against yeast α-glucosidase. In particular, compounds 9c , 9d , and 9h exhibited high anti-α-glucosidase activity. Representatively, compound 9c with IC 50 = 1.3 µM, was 576-times more potent than positive control acarbose. Molecular docking study of the most active compounds showed that these compounds formed important binding interactions at α-glucosidase active site. Molecular dynamics study of compound 9c was also performed and the obtained results were compared with acarbose. Compounds 9c , 9d , and 9h were also evaluated for in silico druglikeness properties and ADMET prediction. These studies showed that the title most potent compounds could be exploited as drug candidates. [ABSTRACT FROM AUTHOR]

[Display omitted] • Investigation of the pH on the adsorption of 5-FU onto functionalized nanocarrier. • This study was done by experimental and molecular dynamics simulation methods. • The blood and cancerous tumor are suitable for 5-FU loading and release, respectively. • 5-FU adsorption on nanocarrier in pH = 7.4 was stronger than it was in pH = 5.0, 9.0. Multi-walled carbon nanotubes (MWCNTs) can be applied for pH-sensitive delivery of anticancer drugs. Due to the importance of 5-fluorouracil (5-FU) in different tumor therapy regimens, it has been widely used in different pH dependent drug delivery systems. To investigate the pH effects on loading (and release) of 5-FU on (and from) the functionalized MWCNTs and propose the optimum condition for drug delivery, both macroscopic and microscopic studies were carried out using chromatography and molecular dynamic simulation at different conditions. For both levels of studies, different analytical approaches were performed to assess the validity of the methods. The experimental results revealed that 5-FU has more binding affinity to the surface of the nanocarrier at physiological pH (pH = 7.4) and showed more release at acidic conditions (pH = 5.0). Meanwhile it has been observed that basic pH (pH = 9.0) can lead to a dramatic decrease effect on loading of the drug. The results of this study can be used to suggest the optimum pH levels for nanocarbon based formulations of 5-FU in cancer therapy. [ABSTRACT FROM AUTHOR]