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Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus’ replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.

In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC50) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC50 inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC50) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and non-covalent inhibitors that simultaneously inhibit the SARS-CoV-2 M-pro and the virus replication in vitro are discussed.

In root canal treatment, post-operative endodontic pain is considered as a common post-operative complication. Knowledge about its causes helps the clinician in proper instrument and technique selection to decrease its incidence. Therefore, the aim of this randomized clinical trial was to compare the post-operative pain occurrence after single visit root canal preparation using ProTaper Universal rotary system or M-Pro rotary system. Eighty patients with symptomatic irreversible pulpitis in mandibular first molars were allocated into two groups. In group A ( n  = 40): root canal preparation was performed using ProTaper Universal system and in group B ( n  = 40): root canal preparation was performed using M-Pro rotary system. Pain level was assessed by the patient using the numerical rating scale (NRS) at 24 h and 7 days postoperatively. The patients were advised to take the prescribed analgesics in case of emergency need. Data and statistical analysis showed that there was significant decrease in pain in both groups after 24 h and after 7 days. Insignificant difference was found between ProTaper Universal group and M-Pro group after 24 h and after 7 days. Insignificant difference was found in analgesics intake between both groups after 24 h and after 7 days. Trial registration: The trial protocol was registered at https://ClinicalTrials.gov (NCT06777381), registered January 15, 2024.

The “Long-COVID syndrome” has posed significant challenges due to a lack of validated therapeutic options. We developed a novel multi-step virtual screening strategy to reliably identify inhibitors against 3-chymotrypsin-like protease of SARS-CoV-2 from abundant flavonoids, which represents a promising source of antiviral and immune-boosting nutrients. We identified 57 interacting residues as contributors to the protein-ligand binding pocket. Their energy interaction profiles constituted the input features for Machine Learning (ML) models. The consensus of 25 classifiers trained using various ML algorithms attained 93.9% accuracy and a 6.4% false-positive-rate. The consensus of 10 regression models for binding energy prediction also achieved a low root-mean-square error of 1.18 kcal/mol. We screened out 120 flavonoid hits first and retained 50 drug-like hits after predefined ADMET filtering to ensure bioavailability and safety profiles. Furthermore, molecular dynamics simulations prioritized nine bioactive flavonoids as promising anti-SARS-CoV-2 agents exhibiting both high structural stability (root-mean-square deviation < 5 Å for 218 ns) and low MM/PBSA binding free energy (<−6 kcal/mol). Among them, KB-2 (PubChem-CID, 14630497) and 9-O-Methylglyceofuran (PubChem-CID, 44257401) displayed excellent binding affinity and desirable pharmacokinetic capabilities. These compounds have great potential to serve as oral nutraceuticals with therapeutic and prophylactic properties as care strategies for patients with long-COVID syndrome.

Introduction: SARS-CoV-2 is a novel coronavirus with highly contagious and has posed a significant threat to global public health. The main protease (M pro ) is a promising target for antiviral drugs against SARS-CoV-2. Methods: In this study, we have used pharmacophore-based drug design technology to identify potential compounds from drug databases as M pro inhibitors. Results: The procedure involves pharmacophore modeling, validation, and pharmacophore-based virtual screening, which identifies 257 compounds with promising inhibitory activity. Discussion: Molecular docking and non-bonding interactions between the targeted protein M pro and compounds showed that ENA482732 was the best compound. These results provided a theoretical foundation for future studies of M pro inhibitors against SARS-CoV-2.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics.

The persistence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of new mutant strains continue to present a substantial threat with potential for future pandemics. Safe, effective, and readily available COVID-19 therapeutics are urgently needed to prepare for future coronavirus pandemics. To help identify new antiviral agents, the present study focused on natural products in the extracts of Holy Basil, Ocimum tenuiflorum L., which show potential inhibitory effects against the SARS-CoV-2 main protease (M pro ). Bioassay-guided isolation of the MeOH extracts of O. tenuiflorum led to the identification of a sulfur-containing glyceroglycolipid, sulfoquinovosyl diacylglycerol (SQDG: 1 ), as a potent M pro inhibitor that effectively inhibited M pro activity (IC 50 : 0.42 µM). SQDG ( 1 ) also markedly suppressed SARS-CoV-2 replication (EC 50 , 51.2 µM) in vitro while displaying no cytotoxicity (CC 50 > 100 µM). Further inhibition kinetic studies and docking simulations clearly demonstrated that SQDG strongly inhibited SARS-CoV-2 M pro in a competitive and mixed-inhibition manner. These findings highlight SQDG as a promising lead compound for COVID-19 therapy and emphasize the need to explore new drugs from natural sources. Graphical Abstract

How do dealers price contemporary art in a world where objective criteria seem absent?Talking Pricesis the first book to examine this question from a sociological perspective. On the basis of a wide range of qualitative and quantitative data, including interviews with art dealers in New York and Amsterdam, Olav Velthuis shows how contemporary art galleries juggle the contradictory logics of art and economics. In doing so, they rely on a highly ritualized business repertoire. For instance, a sharp distinction between a gallery's museumlike front space and its businesslike back space safeguards the separation of art from commerce. Velthuis shows that prices, far from being abstract numbers, convey rich meanings to trading partners that extend well beyond the works of art. A high price may indicate not only the quality of a work but also the identity of collectors who bought it before the artist's reputation was established. Such meanings are far from unequivocal. For some, a high price may be a symbol of status; for others, it is a symbol of fraud. Whereas sociological thought has long viewed prices as reducing qualities to quantities, this pathbreaking and engagingly written book reveals the rich world behind these numerical values. Art dealers distinguish different types of prices and attach moral significance to them. Thus the price mechanism constitutes a symbolic system akin to language.

A witch's curse, an imperialist conspiracy, a racist plot-HIV/AIDS is a catastrophic health crisis with complex cultural dimensions. From small villages to the international system, explanations of where it comes from, who gets it, and who dies are tied to political agendas, religious beliefs, and the psychology of devastating grief. Frequently these explanations conflict with science and clash with prevention and treatment programs. In Witches, Westerners, and HIV Alexander Rödlach draws on a decade of research and work in Zimbabwe to compare beliefs about witchcraft and conspiracy theories surrounding HIV/AIDS in Africa. He shows how both types of beliefs are part of a process of blaming others for AIDS, a process that occurs around the globe but takes on local, culturally specific forms. He also demonstrates the impact of these beliefs on public health and advocacy programs, arguing that cultural misunderstandings contribute to the failure of many well-intentioned efforts. This insightful book provides a cultural perspective essential for everyone interested in AIDS and cross-cultural health issues.

In the United States and throughout the industrialized world, just as the population of older and sicker patients is about to explode, we have a major shortage of nurses. Why are so many RNs dropping out of health care's largest profession? How will the lack of skilled, experienced caregivers affect patients? These are some of the questions addressed by Suzanne Gordon's definitive account of the world's nursing crisis. InNursing against the Odds, one of North America's leading health care journalists draws on in-depth interviews, research studies, and extensive firsthand reporting to help readers better understand the myriad causes of and possible solutions to the current crisis. Gordon examines how health care cost cutting and hospital restructuring undermine the working conditions necessary for quality care. She shows how the historically troubled workplace relationships between RNs and physicians become even more dysfunctional in modern hospitals. In Gordon's view, the public image of nurses continues to suffer from negative media stereotyping in medical shows on television and from shoddy press coverage of the important role RNs play in the delivery of health care. Gordon also identifies the class and status divisions within the profession that hinder a much-needed defense of bedside nursing. She explains why some policy panaceas-hiring more temporary workers, importing RNs from less-developed countries-fail to address the forces that drive nurses out of their workplaces. To promote better care, Gordon calls for a broad agenda that includes safer staffing, improved scheduling, and other policy changes that would give nurses a greater voice at work. She explores how doctors and nurses can collaborate more effectively and what medical and nursing education must do to foster such cooperation. Finally, Gordon outlines ways in which RNs can successfully take their case to the public while campaigning for health care system reform that actually funds necessary nursing care.