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Computational approaches supporting the early characterization of fragment molecular recognition mechanism represent a valuable complement to more expansive and low-throughput experimental techniques. In this retrospective study, we have investigated the geometric accuracy with which high-throughput supervised molecular dynamics simulations (HT-SuMD) can anticipate the experimental bound state for a set of 23 fragments targeting the SARS-CoV-2 main protease. Despite the encouraging results herein reported, in line with those previously described for other MD-based posing approaches, a high number of incorrect binding modes still complicate HT-SuMD routine application. To overcome this limitation, fragment pose stability has been investigated and integrated as part of our in-silico pipeline, allowing us to prioritize only the more reliable predictions., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The A 3 adenosine receptor (AR) is a G protein-coupled receptor (GPCR) overexpressed in the membrane of specific cancer cells. Thus, the development of nanosystems targeting this receptor could be a strategy to both treat and diagnose cancer. Iron-filled carbon nanotubes (CNTs) are an optimal platform for theranostic purposes, and the use of a magnetic field can be exploited for cancer magnetic cell sorting and thermal therapy. In this work, we have conjugated an A 3 AR ligand on the surface of iron-filled CNTs with the aim of targeting cells overexpressing A 3 ARs. In particular, two conjugates bearing PEG linkers of different length were designed. A docking analysis of A 3 AR showed that neither CNT nor linker interferes with ligand binding to the receptor; this was confirmed by in vitro preliminary radioligand competition assays on A 3 AR. Encouraged by this result, magnetic cell sorting was applied to a mixture of cells overexpressing or not the A 3 AR in which our compound displayed indiscriminate binding to all cells. Despite this, it is the first time that a GPCR ligand has been anchored to a magnetic nanosystem, thus it opens the door to new applications for cancer treatment., (© 2020 Wiley-VCH GmbH.)

Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoform δ, with an IC 50 value of 16.1 μm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1δ catalytic activity indeed links the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2)., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Unquestionably, water appears to be an active player in the noncovalent protein-ligand binding process, as it can either bridge interactions between protein and ligand or can be replaced by the bound ligand. Accordingly, in the last decade, alternative computational methodologies have been sought with the aim of predicting the position and thermodynamic profile of water molecules (i.e., hydration sites) in the binding site using either the ligand-bound or ligand-free protein conformation. Herein, we present an alternative approach, named AquaMMapS, that provides a three-dimensional sampling of putative hydration sites. Interestingly, AquaMMapS can post-inspect molecular dynamics (MD) trajectories obtained from different MD engines using indifferently crystallographic or docking-driven structures as a starting point. Moreover, AquaMMapS is naturally integrated into supervised molecular dynamics (SuMD) simulations, presenting the possibility to inspect hydration sites during the ligand-protein association process. Finally, a penalty scoring method, named AquaMMapScoring(AMS), was developed to evaluate the number and nature of the water molecules displaced by a ligand approaching its binding site during the binding event, guiding a medicinal chemist to explore the most suitable regions of a ligand that can be decorated either with or without interfering with the interaction networks mediated by water molecules with specific recognition regions of the protein., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)