Molecular docking is a computational method widely used in drug discovery. Due to the inherent inaccuracies of molecular docking, visual inspection of binding modes is a crucial routine in the ...decision making process of computational medicinal chemists. Despite its apparent importance for medicinal chemistry projects, guidelines for the visual docking pose assessment have been hardly discussed in the literature. Here, we review the medicinal chemistry literature with the aim of identifying consistent principles for visual inspection, highlighting cases of its successful application, and discussing its limitations. In this context, we conducted a survey reaching experts in both academia and the pharmaceutical industry, which also included a challenge to distinguish native from incorrect poses. We were able to collect 93 expert opinions that offer valuable insights into visually supported decision-making processes. This perspective shall motivate discussions among experienced computational medicinal chemists and guide young scientists new to the field to stratify their compounds.
The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health. To this ...date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the identification and development of specific antiviral therapeutics against SARS-CoV-2. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. In order to find novel inhibitors, we computationally screened a compound library of over 606 million compounds for binding at the recently solved crystal structure of the main protease (M
) of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 M
inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of molecular descriptors relevant for pharmacokinetics to narrow down the number of initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of potential off-target binding, we report a list of 12 purchasable compounds, with binding affinity to the target protease that is predicted to be more favorable than that of the cocrystallized peptidomimetic compound. In order to quickly advise ongoing therapeutic intervention for patients, we evaluated approved antiviral drugs and other protease inhibitors to provide a list of nine compounds for drug repurposing. Furthermore, we identified the natural compounds (-)-taxifolin and rhamnetin as potential inhibitors of M
. Rhamnetin is already commercially available in pharmacies.
Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease‐initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are ...characteristic for AD. Here, we analyze the contribution of microRNA‐125b (miR‐125b), which is elevated in AD. In primary neurons, overexpression of miR‐125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42‐MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti‐apoptotic factor Bcl‐W are downregulated as direct targets of miR‐125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl‐W prevents miR‐125b‐induced tau phosphorylation, suggesting that they mediate the effects of miR‐125b on tau. Conversely, suppression of miR‐125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR‐125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl‐W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR‐125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
Synopsis
Altered microRNA expression has been described for brains from Alzheimer's disease (AD) patients. This study links upregulation of miR‐125b to enhanced tau phosphorylation in primary neurons and mouse brains, subsequently leading to impaired learning and memory, both hallmarks of AD.
miR‐125b is elevated in the frontal cortex of AD patients.
miR‐125b overexpression induces tau phosphorylation at multiple sites.
miR‐125b blocks the expression of the phosphatases DUSP6 and PPP1CA as well as the anti‐apoptotic protein Bcl‐W.
Repression of these miR‐125b targets activates the tau kinases cdk5/p35 and Erk1/2.
Injection of miR‐125b into the dentate gyrus of wild‐type mice impairs learning and memory.
Direct regulation of tau kinases and phosphatases by an Alzheimer's disease‐overexpressed miRNA promotes pathological tau phosphorylation and accompanying learning and memory defects.
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can ...be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
Changes in gene expression in the brain may underlie cognitive deficits inherent to normal aging and neurodegenerative disease. However, the mechanisms underlying pathological alterations in the ...brain transcriptome are incompletely understood. Epigenetic mechanisms such as DNA methylation and histone acetylation have been shown to be important for memory processes in the adult brain. There is accumulating evidence that altered chromatin plasticity and histone acetylation are also involved in cognitive aging, neurodegeneration, and neuropsychiatric diseases. Inhibitors of histone deacetylase (HDAC) exhibit neuroprotective and neuroregenerative properties in animal models of various brain diseases. As such, targeting of HDACs seems to be a promising therapeutic strategy. In this review, we discuss the specific roles of each HDAC protein and the possible function of distinct histone modifications. We hope that this knowledge will aid in the development of diagnostic tools and in designing more potent and specific treatment for neurological disorders targeting selective HDAC proteins.
Ligand Pathways in Nuclear Receptors Fischer, André; Smieško, Martin
Journal of chemical information and modeling,
07/2019, Letnik:
59, Številka:
7
Journal Article
Recenzirano
Nuclear receptors (NRs) are ligand-inducible transcription factors that play an essential role in a multitude of physiological processes as well as diseases, rendering them attractive drug targets. ...Crystal structures revealed the binding site of NRs to be buried in the core of the protein, with no obvious route for ligands to access this cavity. The process of ligand binding is known to be an often-neglected contributor to the efficacy of drug candidates and is thought to influence the selectivity and specificity of NRs. While experimental methods generally fail to highlight the dynamic processes of ligand access or egress on the atomistic scale, computational methods have provided fundamental insight into the pathways connecting the buried binding pocket to the surrounding environment. Methods based on molecular dynamics (MD) and Monte Carlo simulations have been applied to identify pathways and quantify their capability to transport ligands. Here, we systematically review findings of more than 20 years of research in the field, including the applied methodology and controversies. Further, we establish a unified nomenclature to describe the pathways with respect to their location relative to protein secondary structure elements and summarize findings relevant to drug design. Lastly, we discuss the effect of NR interaction partners such as coactivators and corepressors, as well as mutations on the pathways.
The figure of Herakles is one of the guiding images of resistance in Peter Weiss's Die Ästhetik des Widerstands. Rather than embodying ideological concepts or utopian perspectives of resistance, ...Herakles is presented as a social myth that, echoing the ideas of Georges Sorel, should inspire resistance against Nazism through the pathos of struggle and defeat. By highlighting the pathos of Herakles, Weiss re-envisions this ambiguous myth in the context of antifascism and connects it with a political iconography of resistance. This essay analyzes the aesthetic and iconological implications of Weiss's use of the Herakles myth through readings of Georges Sorel's theory of social myth, Walter Benjamin's notion of redeeming violence, and Aby Warburg's concept of the pathos formula. By recuperating Herakles through his negative appearance in the Pergamon Altar, and by emphasizing the pathos of suffering, Weiss shows how the aesthetization of politics through fascism can be countered by a politicization of aesthetics that appropriates myth for the antifascist resistance.
The disruptive process of transformation in the audiovisual sector were unexpectedly accelerated after the covid-19 pandemic. This caused a rearrangement in the chain of the distribution, exhibition ...and circulation, restructuring the whole design of film festivals, once considered the launching point of this entire industry and strongly based on specific physical locations. The platformization process permanently changed the traditional model of audiovisual distribution, staffing and curation of festivals - which undergo a hybridization operation that allows the potential use of interactive resources and online delivery of movies, plays and performances to audiences all around the globe. Different narrative strategies in contemporary production using multiple platforms in creative processes are innovating storytelling model and influencing film festival programming and production. The current format of online film festivals restricts access to user data, as the exhibition is limited by parameters established by exhibition licensing agrements and limited tickets per screening. The process of festivals platformization implies new online functionalities integrated at economic and infrastructure levels which fully affects their organization and strategies. MixBrasil Festival is proposing new ways to merge different formats and languages into its programming.
► A proper genome-environment interaction is a pre-requisite for cognitive function. ► We address the role of histone acetylation in age-associated memory impairment and AD. ► Deregulated histone ...acetylation might be causally involved in cognitive diseases. ► We explain why HDAC inhibition could be a treatment strategy of cognitive impairment. ► Stimulus-driven interplay of HATs, HDACs, and metabolism is crucial for memory function.
Learning and memory are cognitive processes that are tightly regulated. A proper genome-environment interaction is a pre-requisite for cognitive function. Epigenetic processes are central regulators of genome-environment interactions. In line with this, it has been shown that the epigenetic machinery is essential for cognitive function. With a specific focus on histone acetylation, we will discuss recent research in the field of epigenetic mechanisms of learning and memory. We will also specifically address the role of histone acetylation in age-associated memory impairment and Alzheimer’s disease and ask the question why targeting the epigenome could be a suitable strategy for neuroprotection and neuroregeneration.
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