With an increasing interest in RNA therapeutics and for targeting RNA to treat disease, there is a need for the tools used in protein-based drug design, particularly DOCKing algorithms, to be ...extended or adapted for nucleic acids. Here, we have compiled a test set of RNA-ligand complexes to validate the ability of the DOCK suite of programs to successfully recreate experimentally determined binding poses. With the optimized parameters and a minimal scoring function, 70% of the test set with less than seven rotatable ligand bonds and 26% of the test set with less than 13 rotatable bonds can be successfully recreated within 2 A heavy-atom RMSD. When DOCKed conformations are rescored with the implicit solvent models AMBER generalized Born with solvent-accessible surface area (GB/SA) and Poisson-Boltzmann with solvent-accessible surface area (PB/SA) in combination with explicit water molecules and sodium counterions, the success rate increases to 80% with PB/SA for less than seven rotatable bonds and 58% with AMBER GB/SA and 47% with PB/SA for less than 13 rotatable bonds. These results indicate that DOCK can indeed be useful for structure-based drug design aimed at RNA. Our studies also suggest that RNA-directed ligands often differ from typical protein-ligand complexes in their electrostatic properties, but these differences can be accommodated through the choice of potential function. In addition, in the course of the study, we explore a variety of newly added DOCK functions, demonstrating the ease with which new functions can be added to address new scientific questions.
We report a case of Zika virus infection imported in Florence, Italy ex-Thailand, leading to a secondary autochthonous case, probably through sexual transmission. The two cases occurred in May 2014 ...but were retrospectively diagnosed in 2016 on the basis of serological tests (plaque reduction neutralisation) performed on stored serum samples. Our report provides further evidence that sexual transmission of Zika virus is possible.
A database consisting of 780 ligand−receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand ...conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 Å criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad docking trends, and the type of failures involved (scoring/sampling), which will likely be of interest to researchers making specific receptor choices for virtual screening. SB2010 is available for download at http://rizzolab.org.
On the positronium g-factor Agil, J.; Battesti, R.; Rizzo, C. ...
The European physical journal. D, Atomic, molecular, and optical physics,
11/2023, Letnik:
77, Številka:
11
Journal Article
Recenzirano
In this letter, we recall the main facts concerning the g-factor of positronium and we show how the value of the g-factor of the positronium is important. Taking it better into consideration may ...provide a solution to the reported discrepancy between QED theory and experiments concerning the hyperfine splitting of the fundamental level of the positronium. We also give the only experimental value that existing experiments can provide,
g
Ps
=
2.0023
±
0.0012
at
3
σ
.
Graphic abstract
Fatty acid binding proteins (FABPs), in particular FABP5 and FABP7, have recently been identified by us as intracellular transporters for the endocannabinoid anandamide (AEA). Furthermore, animal ...studies by others have shown that elevated levels of endocannabinoids resulted in beneficial pharmacological effects on stress, pain and inflammation and also ameliorate the effects of drug withdrawal. Based on these observations, we hypothesized that FABP5 and FABP7 would provide excellent pharmacological targets. Thus, we performed a virtual screening of over one million compounds using DOCK and employed a novel footprint similarity scoring function to identify lead compounds with binding profiles similar to oleic acid, a natural FABP substrate. Forty-eight compounds were purchased based on their footprint similarity scores (FPS) and assayed for biological activity against purified human FABP5 employing a fluorescent displacement-binding assay. Four compounds were found to exhibit approximately 50% inhibition or greater at 10 µM, as good as or better inhibitors of FABP5 than BMS309403, a commercially available inhibitor. The most potent inhibitor, γ-truxillic acid 1-naphthyl ester (ChemDiv 8009-2334), was determined to have K(i) value of 1.19±0.01 µM. Accordingly a novel α-truxillic acid 1-naphthyl mono-ester (SB-FI-26) was synthesized and assayed for its inhibitory activity against FABP5, wherein SB-FI-26 exhibited strong binding (K(i) 0.93±0.08 µM). Additionally, we found SB-FI-26 to act as a potent anti-nociceptive agent with mild anti-inflammatory activity in mice, which strongly supports our hypothesis that the inhibition of FABPs and subsequent elevation of anandamide is a promising new approach to drug discovery. Truxillic acids and their derivatives were also shown by others to have anti-inflammatory and anti-nociceptive effects in mice and to be the active component of Chinese a herbal medicine (Incarvillea sinensis) used to treat rheumatism and pain in humans. Our results provide a likely mechanism by which these compounds exert their effects.
Abstract Objective The aim of this study was to investigate the effects of excess body fat on bone mass in overweight, obese, and extremely obese adolescents. Methods This study included 377 ...adolescents of both sexes, ages 10 to 19 y. Weight, height, body mass index (BMI), bone age, bone mineral content (BMC), and bone mineral density (BMD) were obtained by dual-energy x-ray absorptiometry. The results were adjusted for chronological age and bone age. Comparisons according to nutritional classification were performed by analysis of variance, followed by Tukey test. Linear regression models were used to explain the variation in BMD and BMC in the L1–L4 lumbar spinal region, proximal femur, and whole body in relation to BMI, lean mass, fat mass (FM), and body fat percentage (BF%), considering P < 0.05. Results For all nutritional groups, average bone age was higher than chronological age. In both sexes, weight and BMI values increased from eutrophic to extremely obese groups, except for BMD and BMC, which did not differ among male adolescents, and were smaller in extremely obese than in obese female adolescents ( P < 0.01). Significant differences were observed for FM and BF% values among all nutritional groups ( P < 0.01). Positive, moderate to strong correlations were detected between BMD and BMC for BMI, lean mass, and FM. A negative and moderate correlation was found between BMC and BF%, and between BMD and BF% at all bone sites analyzed in males and between BF% and spine and femur BMD, in females. Conclusion The results reveal a negative effect of BF% on bone mass in males and indicate that the higher the BF% among overweight adolescents, the lower the BMD and BMC values.
Vacuum birefringence experiments: optical noise Agil, J.; Battesti, R.; Rizzo, C.
The European physical journal. D, Atomic, molecular, and optical physics,
2022/10, Letnik:
76, Številka:
10
Journal Article
Recenzirano
In this paper, in the framework of the BMV (
Biréfringence Magnétique du Vide
) project, whose goal is the measurement of the vacuum linear magnetic birefringence, we study the optical noise ...affecting these kinds of experiments by detailing its sources, and we perform experimental measurements of all of them, clarifying that the limiting noise is a birefringence one.
Graphic Abstract
The goal of the quench and partition (Q&P) process for steel heat treatment is to enrich austenite with carbon during a partitioning treatment after initial quenching below the martensite start ...temperature (Ms). Two proposed mechanisms for austenite carbon enrichment during partitioning include carbon transport from martensite and/or the formation of carbide-free bainite. Theoretical calculations show experimentally measured austenite fractions are difficult to explain based upon a mechanism involving solely bainite formation. Carbon partitioning from martensite provides a more satisfactory explanation, although the formation of bainite during partitioning cannot be completely excluded.
We report a study on vector competence of an Italian population of Aedes albopictus for Zika virus (ZIKV). Ae. albopictus was susceptible to ZIKV infection (infection rate: 10%), and the virus could ...disseminate and was secreted in the mosquito's saliva (dissemination rate: 29%; transmission rate: 29%) after an extrinsic incubation period of 11 days. The observed vector competence was lower than that of an Ae. aegypti colony tested in parallel.
Abstract
Pathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 ...converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus
Cryptococcus neoformans
(
Cn
) results in ergosterol 3β-D-glucoside accumulation, renders
Cn
non-pathogenic, and immunizes mice against secondary infections by wild-type
Cn
, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in
Cn
cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the
Cn Δsgl1
mutant and prevents dissemination of wild-type
Cn
to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1.
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