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Leishmaniasis is a public health concern, especially in Brazil and India. The drugs available for therapy are old, cause toxicity and have reports of resistance. Therefore, this paper aimed to carry out initial structure-activity relationships (applying molecular docking and dynamic simulations) of arylindole scaffolds against the pteridine reductase (PTR1), which is essential target for the survival of the parasite. Thus, we used a series of 43 arylindole derivatives as a privileged skeleton, which have been evaluated previously for different biological actions. Compound 7 stood out among its analogues presenting the best results of average number of interactions with binding site (2.00) and catalytic triad (1.00). Additionally, the same compound presented the best binding free energy (−32.33 kcal/mol) in dynamic simulations. Furthermore, with computational studies, it was possible to comprehend and discuss the influences of the substituent sizes, positions of substitutions in the aromatic ring and electronic influences. Therefore, this study can be a starting point for the structural improvements needed to obtain a good leishmanicidal drug. [ABSTRACT FROM AUTHOR]

Overexpression of casein kinase-2 (CK2) has been implicated in several carcinomas, mainly lung, prostate and acute myeloid leukaemia. The smaller nucleotide pocket compared to related kinases provides a great opportunity to discover newer ATP-competitive CK2 inhibitors. In this study, we have employed an integrated structure- and fragment-based design strategy to design 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive CK2 inhibitors. A statistically significant four features-based E-pharmacophore (ARRR) model was used to screen 780,092 molecules. Further, the retrieved hits were considered for molecular docking study to identify essential binding interactions. At the same time, fragment-based virtual screening was performed using a dataset of 1,542,397 fragments. The identified hits and fragments were used as structure templates to rationalize the design of 2-amino-6-methyl-pyrimidine benzoic acids as newer CK2 inhibitors. Finally, the binding interactions of the designed hits were identified using an induced fit docking (IFD) study, and their stability was estimated by a molecular dynamics (MD) simulation study of 100 ns. [ABSTRACT FROM AUTHOR]

A series of some new benzimidazole-1,3,4-thiadiazoles was synthesized. The structures of target substances were confirmed by using 1H-NMR and 13С-NMR spectroscopy, mass spectrometry and elemental analysis. The synthesized compounds were evaluated for antimicrobial activity against six bacterial strains namely Escherichia coli (ATCC 25922), Klebsiella pneumoniae (ATCC 13883), Pseudomonas aeruginosa (ATCC 27853), Enterococcus faecalis (ATCC 2942), Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 29213)and four fungal strains namely Candida albicans (ATCC 24433), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019) and Candida glabrata (ATCC 9). Antimicrobial data revealed that compounds 4f and 4i with MIC of < 0.97 µg/mL were found to be most effective against E. coli. Among the studied molecules, compounds 4f and 4i showed the best antifungal activity with MIC value of 1.95 µg/mL. Additionally, docking studies were performed towards the most promising compounds 4f and 4i, in the active site of DNA gyrase revealing strong interactions. A molecular dynamics (MD) simulation analysis was also used to investigate the dynamic nature, binding interaction, and protein–ligand stability. [ABSTRACT FROM AUTHOR]

Breast cancer has been associated with an overexpression of various molecular targets; accordingly, various target-specific chemotherapeutic agents have been developed. Inhibition of ERK2, a member of MAPK pathway, is an important target involved in the treatment of both oestrogen receptor-positive and triple-negative breast cancer. Thus, in continuation of our previous work on the ERK2 target, we here report novel inhibitors of this kinase. Out of three lead molecules reported in our previous study, we selected the thiazolidinone-pyrimidine scaffold for further development of small molecule inhibitors of ERK2. Analogues of the lead molecule were docked in the target kinase, followed by molecular dynamic simulations and MM-GBSA calculations. Analogues maintaining key interactions with amino acid residues in the ATP-binding domain of ERK2 were selected and duly synthesized. In vitro biochemical evaluation of these molecules against ERK2 kinase disclosed that two molecules possess significant kinase inhibitory potential with IC50 values ≤ 0.5 µM. [ABSTRACT FROM AUTHOR]