Excitation of Slow-Modes in Network Magnetic Elements Through Magnetic Pumping

From radiation magnetohydrodynamic simulations of the solar atmosphere we find a new mechanism for the excitation of longitudinal slow modes within magnetic flux concentrations. We find that the convective downdrafts in the immediate surroundings of magnetic elements are responsible for the excitation of slow modes. The coupling between the external downdraft and the plasma motion internal to the flux concentration is mediated by the inertial forces of the downdraft that act on the magnetic flux concentration. These forces, in conjunction with the downward movement, pump the internal atmosphere in the downward direction, which entails a fast downdraft in the photospheric and chromospheric layers of the magnetic element. Subsequent to the transient pumping phase, the atmosphere rebounds, causing a slow mode traveling along the magnetic flux concentration in the upward direction. It develops into a shock wave in chromospheric heights, possibly capable of producing some kind of dynamic fibril. We propose an observational detection of this process.Comment: 5 pages, 4 figures, accepted for publication in ApJ Lette

Competition NMR for detection of hit/lead inhibitors of protein–protein interactions

Screening for small-molecule fragments that can lead to potent inhibitors of protein-protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low mu M-mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak mu M-mM ligand-protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex's protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.(This article belongs to the Special Issue NMR in the Drug Design

Clinical applications of artificial intelligence in cardiology on the verge of the decade

Artificial intelligence (AI) has been hailed as the fourth industrial revolution and its influence on people’s lives is increasing. The research on AI applications in medicine is progressing rapidly. This revolution shows promise for more precise diagnoses, streamlined workflows, increased accessibility to healthcare services and new insights into ever-growing population-wide datasets. While some applications have already found their way into contemporary patient care, we are still in the early days of the AI-era in medicine. Despite the popularity of these new technologies, many practitioners lack an understanding of AI methods, their benefits, and pitfalls. This review aims to provide information about the general concepts of machine learning (ML) with special focus on the applications of such techniques in cardiovascular medicine. It also sets out the current trends in research related to medical applications of AI. Along with new possibilities, new threats arise — acknowledging and understanding them is as important as understanding the ML methodology itself. Therefore, attention is also paid to the current opinions and guidelines regarding the validation and safety of AI-powered tools

Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery

CA-170 : a potent small-molecule PD-L1 inhibitor or not?

CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 – a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57

Discovery of inhibitory fragments that selectively target Spire2−FMN2 interaction

Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2–FMN2 but not the Spire1–FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H–15N HSQC nuclear magnetic resonance. Extensive structure–activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2–FMN2 interaction

Exploring the Surface of the Ectodomain of the PD-L1 Immune Checkpoint with Small-Molecule Fragments

Development of small molecules targeting the PD-L1/PD-1 interface is advancing both in industry and academia, but only a few have reached early-stage clinical trials. Here, we take a closer look at the general druggability of PD-L1 using in silico hot spot mapping and nuclear magnetic resonance (NMR)-based characterization. We found that the conformational elasticity of the PD-L1 surface strongly influences the formation of hot spots. We deconstructed several generations of known inhibitors into fragments and examined their binding properties using differential scanning fluorimetry (DSF) and protein-based nuclear magnetic resonance (NMR). These biophysical analyses showed that not all fragments bind to the PD-L1 ectodomain despite having the biphenyl scaffold. Although most of the binding fragments induced PD-L1 oligomerization, two compounds, TAH35 and TAH36, retain the monomeric state of proteins upon binding. Additionally, the presence of the entire ectodomain did not affect the binding of the hit compounds and dimerization of PD-L1. The data demonstrated here provide important information on the PD-L1 druggability and the structure-activity relationship of the biphenyl core moiety and therefore may aid in the design of novel inhibitors and focused fragment libraries for PD-L1.This research has been supported by Grants Maestro 2017/26/A/ST5/00572 (to T.A.H.) , Sonata UMO-2020/39/D/ST4/01344 (to E.S.) , Preludium UMO-2021/41/N/ST4/03485 (to M.Z.) , and Preludium UMO-2020/37/N/ST4/02691 (to D.M.) from the National Science Centre, Poland. X.d.C. thanks the Basque Country Government for the predoctoral and EGONLABUR grants