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Background: RON (Recepteur d′Origine Nantais) receptor tyrosine kinase is a promising target for anti‐cancer therapeutics. The aim of this study was to identify new RON inhibitors using virtual screening methods. Methods: To this end, a ligand‐based virtual screening approach was employed for screening of ZINC database on the homology model of RON receptor. All the selected hits were inspected in terms of drug‐likeness, ADME properties, and toxicity profiles. Ligand‐based similarity searches along with further filtering criteria led to the identification of two compounds, TKI1 and TKI2 that were evaluated using in vitro cell‐based RON inhibition assays. Results: The results showed that TKI1 and TKI2 could reduce phosphorylation of RON. Both compounds showed inhibitory activity of the downstream mTOR pathway with no apparent effects on other signaling mediators in a dose‐dependent manner. Conclusion: These compounds can provide a basis for developing novel anti‐RON inhibitors applicable to cancer therapy using medicinal chemistry‐oriented optimization strategies. [ABSTRACT FROM AUTHOR]

To investigate whether peptide sequences with specific translocation across the gastrointestinal barrier can be identified as drug delivery vehicles, in vivo phage display was conducted. For this purpose, a random library of 12‐mer peptides displayed on M13 bacteriophage was orally administered to mice followed by recovery of the phage particles from the blood samples after three consecutive biopanning rounds. The obtained peptide sequences were analyzed using bioinformatics tools and software. The results demonstrated that M13 bacteriophage bearing peptides translocate nonspecifically across the mice intestinal mucosal barrier deduced from random distribution of amino acids in different positions of the identified peptide sequences. The most probable reason for entering the phage particles into systemic circulation after oral administration of the peptide library can be related to the nanoscale nature of their structures which provides a satisfying platform for the purpose of designing nanocarriers in pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Recently, multi‐target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual‐acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6‐chloro‐N‐methyl‐N‐[3‐(4‐methylpiperazin‐1‐yl)propyl]‐1H‐indole‐2‐carboxamide) and compound 4 (7‐chloro‐N‐[(1‐methylpiperidin‐3‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinoline‐2‐carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) containing more than three rings are mainly less biodegradable. Therefore, the isolation of PAHs-degrading bacteria is of great importance to be augmented for bioremediation of polluted sites with PAHs. PAHs-degrading bacteria were isolated from contaminated sites of an oil refinery. The strains were confirmed by biochemical tests and 16S rRNA, which were Stenotrophomonas maltophilia (two strains), Thermomonas koreensis (three strains), Achromobacter (two strains), Pseudomonas stutzeri (one strain), Azospirillum brasilense (one strain) and Brevibacillus brevis (one strain). The isolate strains can be applied as a bacterial consortium for purification of polluted soil with high levels of PAHs. [ABSTRACT FROM AUTHOR]

Histamine H3 receptors (H3R), belonging to G‐protein coupled receptors (GPCR) class A superfamily, are responsible for modulating the release of histamine as well as of other neurotransmitters by a negative feedback mechanism mainly in the central nervous system (CNS). These receptors have gained increased attention as therapeutic target for several CNS related neurological diseases. In the current study, we aimed to identify novel H3R ligands using in silico virtual screening methods. To this end, a combination of ligand‐ and structure‐based approaches was utilized for screening of ZINC database on the homology model of human H3R. Structural similarity‐ and pharmacophore‐based approaches were employed to generate compound libraries. Various molecular modeling methodologies such as molecular docking and dynamics simulation along with different drug likeness filtering criteria were applied to select anti‐H3R ligands as promising candidate molecules based on different known parent lead compounds. In vitro binding assays of the selected molecules demonstrated three of them being active within the micromolar and submicromolar Ki range. The current integrated computational and experimental methods used in this work can provide new general insights for systematic hit identification for novel anti‐H3R agents from large compound libraries. [ABSTRACT FROM AUTHOR]

Aim: This study determined the genes encoding the binding and receiving factors of iron and microbial biofilm in E. coli strains isolated from mucosal samples of patients with colorectal cancer and inflammation of the colorectal compared to healthy people. Background: Colorectal cancer is one of the most important malignancies in recent years. Escherichia coli is the most important infectious agents associated with colorectal cancer that has numerous virulence factors such as iron uptake and adhesion factors included in the process of inflammation and colorectal cancer. Methods: Of the three healthy, inflammatory bowel diseases and colorectal cancer groups, 40 Escherichia coli strains isolated after confirmation by biochemical and molecular methods. After determining the isolates phylogroups, the frequency of genes was measured by PCR method. The biofilm formation of isolates was performed using Crystal Violet method. Results: In the determination of the bacteria phylogroups, the colorectal cancer isolates had a maximum incidence of phylogroups B2 and A. In the analysis of fimH, papA, papC, iutA, ireA and fyuA genes, the highest frequency was observed in these two phylogroups. The presence of ireA gene in bacterial isolates from three groups showed a significant difference (P value: 0.004). There was also no significant difference in biofilm productions in Escherichia coli strains isolated from the three groups. Conclusion: Unlike previous studies focusing solely on Escherichia coli toxins, we found that iron absorption and adhesion factors could be effective in developing inflammatory bowel diseases and colorectal cancer. It was also determined that biofilm formation is a specific characteristic of Escherichia coli isolated from the healthy colon. [ABSTRACT FROM AUTHOR]