Native, engineered and de novo designed ligands targeting the SARS-CoV-2 spike protein.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the deadly coronavirus disease 2019 (Covid-19) and is a concerning hazard to public health. This virus infects cells by establishing a contact between its spike protein (S-protein) and host human angiotensin-converting enzyme 2 (hACE2) receptor, subsequently initiating viral fusion. The inhibition of the interaction between the S-protein and hACE2 has immediately drawn attention amongst the scientific community, and the S-protein was considered the prime target to design vaccines and to develop affinity ligands for diagnostics and therapy.

Discovery of phosphotyrosine-binding oligopeptides with supramolecular target selectivity.

We demonstrate phage-display screening on self-assembled ligands that enables the identification of oligopeptides that selectively bind dynamic supramolecular targets over their unassembled counterparts. The concept is demonstrated through panning of a phage-display oligopeptide library against supramolecular tyrosine-phosphate ligands using 9-fluorenylmethoxycarbonyl-phenylalanine-tyrosine-phosphate (Fmoc-FY) micellar aggregates as targets. The 14 selected peptides showed no sequence consensus but were enriched in cationic and proline residues.

Seeing the Unseen: The Role of Liquid Crystals in Gas-Sensing Technologies.

Fast, real-time detection of gases and volatile organic compounds (VOCs) is an emerging research field relevant to most aspects of modern society, from households to health facilities, industrial units, and military environments. Sensor features such as high sensitivity, selectivity, fast response, and low energy consumption are essential. Liquid crystal (LC)-based sensors fulfill these requirements due to their chemical diversity, inherent self-assembly potential, and reversible molecular order, resulting in tunable stimuliresponsive soft materials.

Free Marine Natural Products Databases for Biotechnology and Bioengineering.

Marine organisms and micro-organisms are a source of natural compounds with unique chemical features. These chemical properties are useful for the discovery of new functions and applications of marine natural products (MNPs). To extensively exploit the potential implementations of MNPs, they are gathered in chemical databases that allow their study and screening for applications of biotechnological interest.

Designed affinity ligands to capture human serum albumin.

Human serum albumin (HSA) in an important therapeutic agent and disease biomarker, with an increasing market demand. By proteins and drugs that bind to HSA as inspiration, a combinatorial library of 64 triazine-based ligands was rationally designed and screened for HSA binding at physiological conditions. Two triazine-based lead ligands (A3A2 and A6A5), presenting more than 50% HSA bound and high enrichment factors, were selected for further studies.

Discovery of new FXR agonists based on 6-ECDCA binding properties by virtual screening and molecular docking.

FXR is a member of the nuclear receptor superfamily, which regulates the expression of various genes involved in bile acid, lipid and glucose metabolism. Targeting FXR with small molecules has been exploited to treat lipid-related disorders and diseases such as cholestasis, gallstones and hepatic disorders. In this work, we expand the existing pool of known FXR agonists using a fast hit-to-lead structure-based pharmacophore and docking screening protocol.

Protein- and Peptide-Based Biosensors in Artificial Olfaction.

Animals' olfactory systems rely on proteins, olfactory receptors (ORs) and odorant-binding proteins (OBPs), as their native sensing units to detect odours. Recent advances demonstrate that these proteins can also be employed as molecular recognition units in gas-phase biosensors. In addition, the interactions between odorant molecules and ORs or OBPs are a source of inspiration for designing peptides with tunable odorant selectivity.

Integration of Molecular Dynamics Based Predictions into the Optimization of De Novo Protein Designs: Limitations and Benefits.

Recent advances in de novo protein design have gained considerable insight from the intrinsic dynamics of proteins, based on the integration of molecular dynamics simulations protocols on the state-of-the-art de novo protein design protocols used nowadays. With this protocol we illustrate how to set up and run a molecular dynamics simulation followed by a functional protein dynamics analysis. New users will be introduced to some useful open-source computational tools, including the GROMACS molecular dynamics simulation software package and ProDy for protein structural dynamics analysis.

Inhibition of human dyskerin as a new approach to target ribosome biogenesis.

The product of the DKC1 gene, dyskerin, is required for both ribosome biogenesis and telomerase complex stabilization. Targeting these cellular processes has been explored for the development of drugs to selectively or preferentially kill cancer cells. Presently, intense research is conducted involving the identification of new biological targets whose modulation may simultaneously interfere with multiple cellular functions that are known to be hyper-activated by neoplastic transformations.

ADP-ribosylated proteins as old and new drug targets for anticancer therapy: the example of ARF6.

Post-translational modifications of cellular proteins by mono- or poly-ADP-ribosylation are associated with numerous cellular processes. ADP-ribosylation reactions are important in the nucleus, and in mitochondrial activity, stress response signaling, intracellular trafficking, and cell senescence and apoptosis decisions. These reversible reactions add ADP-ribose to target proteins via specific enzymes to form the ADP-ribosylated protein; the cleaveage of this covalent bond is performed via hydrolases.

Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives.

Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies.

The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study.

The functional serotonin 5-HT type-3 (5-HT(3)) receptor, the target of many neuroactive drugs, is known to be a pseudo-symmetric pentamer made either of five identical subunits A (homomeric 5-HT(3A)-R) or of subunits A and B (heteromeric 5-HT(3A/B)-R) in a still debated arrangement. The serotonin binding site is located in the extracellular region, at the interface between two monomers, called the principal and the complementary subunits. The results of molecular dynamics simulations and computational alanine scanning mutagenesis studies applied here to the homomeric human 5-HT(3A)-R disclose an aromatic "hot" cluster in the centre of the interface formed by residues W178 (principal subunit), Y68, Y83, W85 and Y148 (complementary subunit).

Comparative analysis of pharmacophore screening tools.

The pharmacophore concept is of central importance in computer-aided drug design (CADD) mainly because of its successful application in medicinal chemistry and, in particular, high-throughput virtual screening (HTVS). The simplicity of the pharmacophore definition enables the complexity of molecular interactions between ligand and receptor to be reduced to a handful set of features. With many pharmacophore screening softwares available, it is of the utmost interest to explore the behavior of these tools when applied to different biological systems.

CoCoCo: a free suite of multiconformational chemical databases for high-throughput virtual screening purposes.

In the last few decades, virtual screening has proved to be able to guide the selection of new hit compounds with predefined biological activity. However, the usage of these computational techniques is often associated with resource- and time-consuming preparation protocols. In this work we present Commercial Compound Collection (CoCoCo), a suite of free and ready-to-use chemical databases to help setting up in silico screening projects.