Haste makes waste: A critical review of docking-based virtual screening in drug repurposing for SARS-CoV-2 main protease (M-pro) inhibition.

This review makes a critical evaluation of 61 peer-reviewed manuscripts that use a docking step in a virtual screening (VS) protocol to predict SARS-CoV-2 M-pro (M-pro) inhibitors in approved or investigational drugs. Various manuscripts predict different compounds, even when they use a similar initial dataset and methodology, and most of them do not validate their methodology or results. In addition, a set of known 150 SARS-CoV-2 M-pro inhibitors extracted from the literature and a second set of 81 M-pro inhibitors and 113 inactive compounds obtained from the COVID Moonshot project were used to evaluate the reliability of using docking scores as feasible predictors of the potency of a SARS-CoV-2 M-pro inhibitor. Using two SARS-CoV-2 M-pro structures and five protein-ligand docking programs, we proved that the correlation between the pIC50 and docking scores is not good. Neither was any correlation found between the pIC50 and the ∆G calculated with an MM-GBSA method. When a group of experimentally known inactive compounds was added, neither the docking scores or the ∆G were able to distinguish between compounds with or without M-pro experimental inhibitory activity. Performances improved when covalent and noncovalent inhibitors were treated separately, but were not good enough to fully support using a docking score as a cutoff value for selecting new putative M-pro inhibitors or predicting the relative bioactivity of a compound by comparison with a reference compound. The two sets of known SARS-CoV-2 M-pro inhibitors presented here could be used for validating future VS protocols which aim to predict M-pro inhibitors.

Bibliometric Analysis on Supercritical CO2 Power Cycles for Concentrating Solar Power Applications.

In recent years, supercritical CO2 power cycles have received a large amount of interest due to their exceptional theoretical conversion efficiency above 50%, which is leading a revolution in power cycle research. Furthermore, this high efficiency can be achieved at a moderate temperature level, thus suiting concentrating solar power (CSP) applications, which are seen as a core business within supercritical technologies. In this context, numerous studies have been published, creating the need for a thorough analysis to identify research areas of interest and the main researchers in the field. In this work, a bibliometric analysis of supercritical CO2 for CSP applications was undertaken considering all indexed publications within the Web of Science between 1990 and 2020. The main researchers and areas of interest were identified through network mapping and text mining techniques, thus providing the reader with an unbiased overview of sCO2 research activities. The results of the review were compared with the most recent research projects and programs on sCO2 for CSP applications. It was found that popular research areas in this topic are related to optimization and thermodynamics analysis, which reflects the significance of power cycle configuration and working conditions. Growing interest in medium temperature applications and the design of sCO2 heat exchangers was also identified through density visualization maps and confirmed by a review of research projects.

Identification of Broad-Spectrum MMP Inhibitors by Virtual Screening.

Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading extracellular matrix (ECM) components. In the skin, the overexpression of MMPs as a result of ultraviolet radiation triggers an imbalance in the ECM turnover in a process called photoaging, which ultimately results in skin wrinkling and premature skin ageing. Therefore, the inhibition of different enzymes of the MMP family at a topical level could have positive implications for photoaging. Considering that the MMP catalytic region is mostly conserved across different enzymes of the MMP family, in this study we aimed to design a virtual screening (VS) workflow to identify broad-spectrum MMP inhibitors that can be used to delay the development of photoaging. Our in silico approach was validated in vitro with 20 VS hits from the Specs library that were not only structurally different from one another but also from known MMP inhibitors. In this bioactivity assay, 18 of the 20 compounds inhibit at least one of the assayed MMPs at 100 µM (with 5 of them showing around 50% inhibition in all the tested MMPs at this concentration). Finally, this VS was used to identify natural products that have the potential to act as broad-spectrum MMP inhibitors and be used as a treatment for photoaging.

Anti-Inflammatory and Immunomodulatory Effects of the Grifola frondosa Natural Compound o-Orsellinaldehyde on LPS-Challenged Murine Primary Glial Cells. Roles of NF-κß and MAPK.

In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when constantly activated, this process can become detrimental through the release of neurotoxic factors that amplify underlying disease. In consequence, this study presents the anti-inflammatory and immunomodulatory properties of o-orsellinaldehyde, a natural compound found by an in silico approach in the Grifola frondosa mushroom, in astrocytes and microglia cells. For this purpose, primary microglia and astrocytes were isolated from mice brain and cultured in vitro. Subsequently, cells were exposed to LPS in the absence or presence of increasing concentrations of this natural compound. Specifically, the results shown that o-orsellinaldehyde strongly inhibits the LPS-induced inflammatory response in astrocytes and microglia by decreasing nitrite formation and downregulating iNOS and HO-1 expression. Furthermore, in microglia cells o-orsellinaldehyde inhibits NF-κB activation; and potently counteracts LPS-mediated p38 kinase and JNK phosphorylation (MAPK). In this regard, o-orsellinaldehyde treatment also induces a significant cell immunomodulation by repolarizing microglia toward the M2 anti-inflammatory phenotype. Altogether, these results could partially explain the reported beneficial effects of G. frondosa extracts on inflammatory conditions.

End of Life Intervention Program During COVID-19 in Vall d'Hebron University Hospital.

Introduction: The coronavirus disease 19 (COVID-19) and its consequences have placed our societies and healthcare systems under pressure. Also, a major impact on the individual and societal experience of death, dying, and bereavement has been observed. Factors such as social distancing, unexpected death or not being able to say goodbye, which might predict Prolonged Grief Disorder (PGD), are taking place. Moreover, hospitals have become a habitual place for End of Life (EOL) situations but not in the usual conditions because, for example, mitigation measures prevent families from being together with hospitalized relatives. Therefore, we implemented an EOL program with a multidisciplinary team involving health social workers (HSW) and clinical psychologists (CP) in coordination with the medical teams and nursing staff. Objectives: We aim to describe an EOL intervention program implemented during COVID-19 in the Vall d'Hebron University Hospital (HUVH). We present its structure, circuit, and functions. Descriptive analyses of the sample and the interventions that required psychological and social attention are reported. Material and methods: The total sample consists of 359 relatives of 219 EOL patients. Inclusion criteria were families cared for during the COVID-19 pandemic with family patients admitted to the HUVH in an EOL situation regardless of whether or not the patient was diagnosed with COVID-19. Results: Our program is based on family EOL care perceptions and the COVID-19 context features that hinder EOL situations. The program attended 219 families, of which 55.3% were COVID-19 patients and 44.7% had other pathologies. The EOL intervention program was activated in most of the EOL situations, specifically, in 85% of cases, and 78% of relatives were able to come and say goodbye to their loved ones. An emotional impact on the EOL team was reported. It is necessary to dignify the EOL situation in the COVID-19 pandemic, and appropriate psychosocial attention is needed to try to minimize future complications in grief processes and mitigate PGD.

Optimization of a New Design of Molten Salt-to-CO2 Heat Exchanger Using Exergy Destruction Minimization.

One of the ways to make cost-competitive electricity, from concentrated solar thermal energy, is increasing the thermoelectric conversion efficiency. To achieve this objective, the most promising scheme is a molten salt central receiver, coupled to a supercritical carbon dioxide cycle. A key element to be developed in this scheme is the molten salt-to-CO2 heat exchanger. This paper presents a heat exchanger design that avoids the molten salt plugging and the mechanical stress due to the high pressure of the CO2, while improving the heat transfer of the supercritical phase, due to its compactness with a high heat transfer area. This design is based on a honeycomb-like configuration, in which a thermal unit consists of a circular channel for the molten salt surrounded by six smaller trapezoidal ducts for the CO2. Further, an optimization based on the exergy destruction minimization has been accomplished, obtained the best working conditions of this heat exchanger: a temperature approach of 50 °C between both streams and a CO2 pressure drop of 2.7 bar.

Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition.

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.

The Light and Dark Sides of Virtual Screening: What Is There to Know?

Virtual screening consists of using computational tools to predict potentially bioactive compounds from files containing large libraries of small molecules. Virtual screening is becoming increasingly popular in the field of drug discovery as in silico techniques are continuously being developed, improved, and made available. As most of these techniques are easy to use, both private and public organizations apply virtual screening methodologies to save resources in the laboratory. However, it is often the case that the techniques implemented in virtual screening workflows are restricted to those that the research team knows. Moreover, although the software is often easy to use, each methodology has a series of drawbacks that should be avoided so that false results or artifacts are not produced. Here, we review the most common methodologies used in virtual screening workflows in order to both introduce the inexperienced researcher to new methodologies and advise the experienced researcher on how to prevent common mistakes and the improper usage of virtual screening methodologies.

Anti-inflammatory and Proapoptotic Properties of the Natural Compound o-Orsellinaldehyde.

Metabolic syndrome is a cluster of medical conditions that increases the risk of developing cardiovascular disease and type 2 diabetes. Numerous studies have shown that inflammation is directly involved in the onset of metabolic syndrome and related pathologies. In this study, in silico techniques were applied to a natural products database containing molecules isolated from mushrooms from the Catalan forests to predict molecules that can act as human nuclear-factor κß kinase 2 (IKK-2) inhibitors. IKK-2 is the main component responsible for activating the nuclear-factor κß transcription factor (NF-κß). One of these predicted molecules was o-orsellinaldehyde, a molecule present in the mushroom Grifola frondosa. This study shows that o-orsellinaldehyde presents anti-inflammatory and pro-apoptotic properties by acting as IKK-2 inhibitor. Additionally, we suggest that the anti-inflammatory and pro-apoptotic properties of Grifola frondosa mushroom could partially be explained by the presence of o-orsellinaldehyde on its composition.

Combined Ligand- and Receptor-Based Virtual Screening Methodology to Identify Structurally Diverse Protein Tyrosine Phosphatase 1B Inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for diabetes and obesity. However, the design of PTP1B inhibitors that combine potency and bioavailability is a great challenge, and new leads are needed to circumvent this problem. Virtual screening (VS) workflows can be used to find new PTP1B inhibitors with little chemical similarity to existing inhibitors. Unfortunately, previous VS workflows for the identification of PTP1B inhibitors have several limitations, such as a small number of experimentally tested compounds and the low bioactivity of those compounds. We developed a VS workflow capable of identifying 15 structurally diverse PTP1B inhibitors from 20 compounds, the bioactivity of which was tested in vitro. Moreover, we identified two PTP1B inhibitors with the highest bioactivity reported by any VS campaign (i.e., IC50 values of 1.4 and 2.1 µm), which could be used as new lead compounds.

Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening.

The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

Resveratrol Potently Counteracts Quercetin Starvation-Induced Autophagy and Sensitizes HepG2 Cancer Cells to Apoptosis.

SCOPE: Resveratrol (RSV) has been described as a potent antioxidant, antisteatotic, and antitumor compound, and it has also been identified as a potent autophagy inducer. On the other hand, quercetin (QCT) is a dietary flavonoid with known antitumor, anti-inflammatory, and antidiabetic effects. Additionally, QCT increases autophagy. To study the hypothetical synergistic effect of both compounds, we test the combined effect of QCT and RSV on the autophagy process in HepG2 cells. METHODS AND RESULTS: Autophagy is studied by western blotting, real-time RT-PCR, and cellular staining. Our results clearly indicate a bifunctional molecular effect of RSV. Both polyphenols are individually able to promote autophagy. Strikingly, when RSV is combined with QCT, it promotes a potent reduction of QCT-induced autophagy and influences proapoptotic signaling. CONCLUSION: RSV acts differentially on the autophagic process depending on the cellular energetic state. We further characterize the molecular mechanisms related to this effect, and we observe that AMP-activated protein kinase (AMPK) phosphorylation, heme oxygenase 1 (HO-1) downregulation, lysosomal membrane permeabilization (LMP), and Zinc (Zn2+ ) dynamics could be important modulators of such RSV-related effects and could globally represent a promising strategy to sensitize cancer cells to QCT treatment.

Ephedrine as a lead compound for the development of new DPP-IV inhibitors.

AIM: Extracts from Ephedra species have been reported to be effective as antidiabetics. A previous in silico study predicted that ephedrine and five ephedrine derivatives could contribute to the described antidiabetic effect of Ephedra extracts by inhibiting dipeptidyl peptidase IV (DPP-IV). Finding selective DPP-IV inhibitors is a current therapeutic strategy for Type 2 diabetes mellitus management. Therefore, the main aim of this work is to experimentally determine whether these alkaloids are DPP-IV inhibitors. Materials & methods: The DPP-IV inhibition of Ephedra's alkaloids was determined via a competitive-binding assay. Then, computational analyses were used in order to find out the protein-ligand interactions and to perform a lead optimization. RESULTS: Our results show that all six molecules are DPP-IV inhibitors, with IC50 ranging from 124 µM for ephedrine to 28 mM for N-methylpseudoephedrine. CONCLUSION: Further computational analysis shows how Ephedra's alkaloids could be used as promising lead molecules for designing more potent and selective DPP-IV inhibitors.

High mortality in patients with influenza A pH1N1 2009 admitted to a pediatric intensive care unit: a predictive model of mortality.

OBJECTIVE: To describe the clinical characteristics and outcome of patients admitted to pediatric intensive care with influenza A (pH1N1) 2009 in Argentina. DESIGN: Retrospective observational study. SETTING: Thirteen pediatric intensive care units in Argentina. SUBJECTS: One hundred and forty-two patients with confirmed or suspected influenza A (H1N1). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 142 critically ill patients. The median age was 19 months (range, 2-110 months) with 39% of the patients <24 months of age. Ninety-nine patients (70%) had an underlying disease. Influenza A (pH1N1) 2009 infection was confirmed in 90 patients and the remaining 52 had a positive direct immunofluorescence assay for influenza A. The median length of stay in the pediatric intensive care unit was 12 days (range, 2-52 days). One hundred eighteen patients (83%) received invasive mechanical ventilation and 19 patients were treated with noninvasive ventilation; however, seven of the patients receiving noninvasive ventilation later needed mechanical ventilation. Sixty-eight patients died (47%) with the most frequent cause refractory hypoxemia. Multivariate logistic regression analysis showed that age <24 months (odds ratio, 2.87; 2.35-3.93), asthma (odds ratio, 1.34; 1.20-2.91), and respiratory coinfection with respiratory syncytial virus (odds ratio, 2.92; 1.20-4.10) were associated with higher mortality. As expected, mechanical ventilation and treatment with inotropes were also associated with increased mortality. CONCLUSIONS: The mortality of children admitted to the pediatric intensive care unit with 2009 pH1N1 influenza was high (47%) in our population. Age <24 months, asthma, respiratory coinfection, need of mechanical ventilation, and treatment with inotropes were predictors of poorer outcome.