There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus’ main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.

Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus’s genome. However, its exact action mechanism, and that of other nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a “delayed” termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1′-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands.

Molecular dynamics simulations are used to unravel the SARS-CoV-2 NSP13 behavior in interaction with natural ligands and inhibitors.

This review is devoted to discussing recent progress on the structure, thermodynamic, reactivity, and dynamics of water and aqueous systems confined within different types of nanopores, synthetic and biological. Currently, this is a branch of water science that has attracted enormous attention of researchers from different fields interested to extend the understanding of the anomalous properties of bulk water to the nanoscopic domain. From a fundamental perspective, the interactions of water and solutes with a confining surface dramatically modify the liquid's structure and, consequently, both its thermodynamical and dynamical behaviors, breaking the validity of the classical thermodynamic and phenomenological description of the transport properties of aqueous systems. Additionally, man-made nanopores and porous materials have emerged as promising solutions to challenging problems such as water purification, biosensing, nanofluidic logic and gating, and energy storage and conversion, while aquaporin, ion channels, and nuclear pore complex nanopores regulate many biological functions such as the conduction of water, the generation of action potentials, and the storage of genetic material. In this work, the more recent experimental and molecular simulations advances in this exciting and rapidly evolving field will be reported and critically discussed.

We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dynamical propensity in simulations that differs markedly form their state-value (that is, formed/not formed) in the PDB structure of the apo protein. To this end, we conduct a series of hydrogen bond propensity calculations in different contexts: 1) computational alanine-scanning studies of the MDM2-p53 interface; 2) the formation of the complex of MDM2 with the disruptive small molecule Nutlin-3a (dissecting the contribution of the different molecular fragments) and 3) the binding of a series of small molecules (drugs) with different affinities for MDM2. Thus, the relevance of the hydrogen bond propensity analysis for protein binding studies and as a useful tool to complement existing methods for drug design and optimization will be made evident.

A versatile and highly efficient strategy to construct a xanthone skeleton via a ligand-free intermolecular catalytic coupling of 2-substituted benzaldehydes and a wide range of phenols has been developed. For this purpose, a novel and magnetically recoverable catalyst consisting of copper nanoparticles on nanosized silica coated maghemite is presented. The reaction proceeds smoothly with easy recovery and reuse of the catalyst. The methodology is compatible with various functional groups and provides an attractive protocol for the generation of a small library of xanthones in very good yield.

We carry out a time-averaged contact matrix study to reveal the existence of protein backbone hydrogen bonds (BHBs) whose net persistence in time differs markedly form their corresponding PDB-reported state. We term such interactions as "chameleonic" BHBs, CBHBs, precisely to account for their tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. We also find a significant enrichment of protein binding sites in CBHBs, relate them to local water exposure and analyze their behavior as ligand/drug targets. Thus, the dynamic analysis of hydrogen bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design.

The interactions between the receptor binding domain (RBD) of SARS-CoV-2 and the angiotensin- converting enzyme 2 (ACE2) are crucial for viral entry and subsequent replication. Given the large and featureless...