Current Issue : October - December Volume : 2018 Issue Number : 4 Articles : 5 Articles
As part of our research for new leads against human African trypanosomiasis (HAT),\nwe report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type\nalkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae),\nsome of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity\nagainst mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena\nalkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were\nobtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in\nterms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal\ncross-validation (leave-one-out), and external predictions (test set), respectively, as well as the\ncorresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83\nand P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat\nskeletal myoblasts, both models were of good internal and external predictive power. The regression\ncoefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr\nand for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing\nsuggestions for possible modification of the aminosteroids to further increase the antitrypanosomal\npotency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena\nalkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds\nrecently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these\nstructurally similar natural products share a common structureââ?¬â??activity relationship (SAR) and,\npossibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in\nplausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroidand\naminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent\na starting point for lead optimization....
The article describes the use of facile one-pot, high-yielding reactions to synthesize\nsubstituted 3,4-dimethyl-1H-pyrrole-2-carboxamides 3aââ?¬â??m and carbohydrazide analogues 5aââ?¬â??l as\npotential antifungal and antimicrobial agents. The structural identity and purity of the synthesized\ncompounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds\nwere assessed in vitro for antifungal and antibacterial activity. The compounds 5h, 5i and 5j\nwere found to be the most potent against Aspergillus fumigatus, with MIC values of 0.039 mg/mL.\nThe compound 5f bearing a 2, 6-dichloro group on the phenyl ring was found to be the most active\nbroad spectrum antibacterial agent with a MIC value of 0.039 mg/mL. The mode of action of the most\npromising antifungal compounds (one representative from each series; 3j and 5h) was established by\ntheir molecular docking with the active site of sterol 14Ã?±-demethylase. Molecular docking studies\nrevealed a highly spontaneous binding ability of the tested compounds in the access channel away\nfrom catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this\nenzyme and would avoid heme iron-related deleterious side effects observed with many existing\nantifungal compounds....
Ticks cause approximately $17ââ?¬â??19 billion economic losses to the livestock industry globally. Development of recombinant\nantitick vaccine is greatly hindered by insufficient knowledge and understanding of proteins expressed by ticks. Ticks secrete\nimmunosuppressant proteins that modulate the hostââ?¬â?¢s immune system during blood feeding; these molecules could be a target for\nantivector vaccine development. Recombinant p36, a 36 kDa immunosuppressor from the saliva of female Dermacentor andersoni,\nsuppresses T-lymphocytes proliferation in vitro. To identify potential unique structural and dynamic properties responsible for\nthe immunosuppressive function of p36 proteins, this study utilized bioinformatic tool to characterize and model structure of\nD. andersoni p36 protein. Evaluation of p36 protein family as suitable vaccine antigens predicted a p36 homolog in Rhipicephalus\nappendiculatus, the tick vector of East Coast fever,with an antigenicity score of 0.7701 that compareswell with that of Bm86 (0.7681),\nthe protein antigen that constitute commercial tick vaccine Tickgard. Ab initio modeling of the D. andersoni p36 protein yielded\na 3D structure that predicted conserved antigenic region, which has potential of binding immunomodulating ligands including\nglycerol and lactose, found located within exposed loop, suggesting a likely role in immunosuppressive functionof tickp36proteins.\nLaboratory confirmation of these preliminary results is necessary in future studies....
SortaseB (SrtB) plays a critical role in Staphylococcus aureus (S. aureus) infections. According\nto the reports in the literature, SrtB can anchor the IsdC to the cell wall to capture iron from the\nhost to achieve a successful invasion. On the other hand, SrtB could also affect the adhesion of S.\naureus to host cells based on previous studies. Here, we report about a novel SrtB inhibitor, coptisine,\na natural compound that does not exhibit antibacterial activity but can inhibit the SrtB activity\nin vitro. A cytotoxicity test indicated that coptisine protects human lung epithelial cells from S. aureus.\nIn addition, coptisine can reduce the adhesion of S. aureus to human lung epithelial cells based on\nthe result of plate colony counting assay. Molecular dynamics simulation revealed that coptisine\ncan bind to the active pocket of SrtB, leading to its activity loss. Through the calculation of binding\nfree energy between ligand and protein, site-directed mutagenesis and fluorescence spectroscopy\nquenching methods, it was confirmed that residues of Arg115, Asn116, and Ile182 played a vital\nrole in the interaction of SrtB with coptisine. These data provide the theoretical basis for the therapy\noption to the infections caused by S. aureus...
Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic.\nApproximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and\ndebilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives\nfollowing hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema\nbeginning in his early 30s. Interestingly, both the individualââ?¬â?¢s 41-year-old sister and 12-year-old daughter were also affected with\nchronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a\nheterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected meAntoneicka L. Harris, Patrick R. Blackburn,\nJohn E. Richter Jr., et al., ââ?¬Å?Whole Exome Sequencing and Molecular\nModeling of a Missense Variant in TNFAIP3 That Segregates with\nDisease in a Family with Chronic Urticaria and Angioedema,ââ?¬Â Case\nReports in Genetics, vol. 2018, Article ID 6968395, 6 pages, 2018.\nhttps://doi.org/10.1155/2018/6968395, https://\ncreativecommons.org/licenses/by/4.0/.mbers.\nVariants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic\nfever syndromes, suggesting that this variant could potentially play a role in disease....
Loading....