Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

The 3CL-Protease appears to be a very promising medicinal target to develop anti-SARS-CoV-2 agents. The availability of resolved structures allows structure-based computational approaches to be carried out even though the lack of known inhibitors prevents a proper validation of the performed simulations. The innovative idea of the study is to exploit known inhibitors of SARS-CoV 3CL-Pro as a training set to perform and validate multiple virtual screening campaigns. Docking simulations using four different programs (Fred, Glide, LiGen, and PLANTS) were performed investigating the role of both multiple binding modes (by binding space) and multiple isomers/states (by developing the corresponding isomeric space). The computed docking scores were used to develop consensus models, which allow an in-depth comparison of the resulting performances. On average, the reached performances revealed the different sensitivity to isomeric differences and multiple binding modes between the four docking engines. In detail, Glide and LiGen are the tools that best benefit from isomeric and binding space, respectively, while Fred is the most insensitive program. The obtained results emphasize the fruitful role of combining various docking tools to optimize the predictive performances. Taken together, the performed simulations allowed the rational development of highly performing virtual screening workflows, which could be further optimized by considering different 3CL-Pro structures and, more importantly, by including true SARS-CoV-2 3CL-Pro inhibitors (as learning set) when available.     

Volatiles and Antifungal-Antibacterial-Antiviral Activity of South African Salvia spp. Essential Oils Cultivated in Uniform Conditions

Spontaneous emissions of S. dentata Aiton and S. scabra Thunb., as well as the essential oil (EO) composition of the cited species, together with S. aurea L., were investigated. The chemical profile of the first two species is reported here for the first time. Moreover, in vitro tests were performed to evaluate the antifungal activity of these EOs on Trichophyton mentagrophytes, Microsporum canis, Aspergillus flavus, Aspergillus niger, and Fusarium solani. Secondly, the EO antibacterial activity against Escherichia coli, Staphylococcus aureus, and Staphylococcus pseudointermedius was examined, and their antiviral efficacy against the H1N1 influenza virus was assessed. Leaf volatile organic compounds (VOCs), as well as the EOs obtained from the arial part of Salvia scabra, were characterized by a high percentage of sesquiterpene hydrocarbons (97.8% and 76.6%, respectively), mostly represented by an equal amount of germacrene D (32.8% and 32.7%, respectively). Both leaf and flower spontaneous emissions of S. dentata, as well as the EO composition, showed a prevalence of monoterpenes divided into a more or less equal amount of hydrocarbon and oxygenated compounds. Interestingly, its EO had a non-negligible percentage of oxygenated sesquiterpenes (29.5%). S. aurea EO, on the contrary, was rich in sesquiterpenes, both hydrocarbons and oxygenated compounds (41.5% and 33.5%, respectively). S. dentata EO showed good efficacy (Minimal Inhibitory Concentration (MIC): 0.5%) against M. canis. The tested EOs were not active against E. coli and S. aureus, whereas a low inhibition of S. dentata EO was observed on S. pseudointermedius (MIC = 10%). Once again, S. dentata EO showed a very good H1N1 inhibition; contrariwise, S. aurea EO was completely inactive against this virus. The low quantity of S. scabra EO made it impossible to test its biological activity. S. dentata EO exhibited interesting new perspectives for medicinal and industrial uses.     

Hydrogen Peroxide Detection Using Prussian Blue-modified 3D Pyrolytic Carbon Microelectrodes

A highly sensitive amperometric Prussian blue-based hydrogen peroxide sensor was developed using 3D pyrolytic carbon microelectrodes. A 3D printed multielectrode electrochemical cell enabled simultaneous highly reproducible Prussian blue modification on multiple carbon electrodes. The effect of oxygen plasma pre-treatment and deposition time on Prussian blue electrodeposition was studied. The amperometric response of 2D and 3D sensors to the addition of hydrogen peroxide in μM and sub-μM concentrations in phosphate buffer was investigated. A high sensitivity comparable to flow injection systems and a detection limit of 0.16 μM was demonstrated with 3D pyrolytic carbon microelectrodes at stirred batch condition     

Thermal conductivity of isolated and interacting carbon nanotubes: comparing results from molecular dynamics and the boltzmann transport equation

We investigate the thermal conductivity of single-wall carbon nanotubes (SWCNT) either isolated or in contact with external media by using equilibrium molecular dynamics and the Boltzmann transport equation. We show that, contrary to existing controversies, both methods yield a finite value of the thermal conductivity for infinitely long tubes, as opposed to the case of 1D, momentum-conserving systems. Acoustic and flexure modes with mean free paths of the order of a few microns are identified as major contributors to the high value of SWCNT conductivity. We also find that the interaction with an external medium may substantially decrease the lifetime of the low-frequency vibrations, reducing the thermal conductivity by up to 2 orders of magnitude.     

Carbon Dioxide as a Protecting Group: Highly Efficient and Selective Catalytic Access to Cyclic cis‐Diol Scaffolds

The efficient and highly selective formation of a wide range of (hetero)cyclic cis‐diol scaffolds using aminotriphenolate‐based metal catalysts is reported. The key intermediates are cyclic carbonates, which are obtained in high yield and with high levels of diastereo‐ and chemoselectivity from the parent oxirane precursors and carbon dioxide. Deprotection of the carbonate structures affords synthetically useful cis‐diol scaffolds with different ring sizes that incorporate various functional groups. This atom‐efficient method allows the simple construction of diol synthons using inexpensive and accessible precursors and green metal catalysts and showcases the use of CO₂ as a temporary protecting group.     

PyCDFT: A Python package for constrained density functional theory

We present PyCDFT, a Python package to compute diabatic states using constrained density functional theory (CDFT). PyCDFT provides an object-oriented, customizable implementation of CDFT, and allows for both single-point self-consistent-field calculations and geometry optimizations. PyCDFT is designed to interface with existing density functional theory (DFT) codes to perform CDFT calculations where constraint potentials are added to the Kohn–Sham Hamiltonian. Here, we demonstrate the use of PyCDFT by performing calculations with a massively parallel first-principles molecular dynamics code, Qbox, and we benchmark its accuracy by computing the electronic coupling between diabatic states for a set of organic molecules. We show that PyCDFT yields results in agreement with existing implementations and is a robust and flexible package for performing CDFT calculations. The program is available at https://dx.doi.org/10.5281/zenodo.3821097 .     

Encapsulation of Flavours and Fragrances into Polymeric Capsules and Cyclodextrins Inclusion Complexes: An Update

Flavours and fragrances are volatile compounds of large interest for different applications. Due to their high tendency of evaporation and, in most cases, poor chemical stability, these compounds need to be encapsulated for handling and industrial processing. Encapsulation, indeed, resulted in being effective at overcoming the main concerns related to volatile compound manipulation, and several industrial products contain flavours and fragrances in an encapsulated form for the final usage of customers. Although several organic or inorganic materials have been investigated for the production of coated micro- or nanosystems intended for the encapsulation of fragrances and flavours, polymeric coating, leading to the formation of micro- or nanocapsules with a core-shell architecture, as well as a molecular inclusion complexation with cyclodextrins, are still the most used. The present review aims to summarise the recent literature about the encapsulation of fragrances and flavours into polymeric micro- or nanocapsules or inclusion complexes with cyclodextrins, with a focus on methods for micro/nanoencapsulation and applications in the different technological fields, including the textile, cosmetic, food and paper industries.     

meso‐(2‐Pyridyl)‐boron(III)‐subporphyrin: Perimeter Iridium(III) Coordination

Peripherally metalated porphyrinoids are promising functional π‐systems displaying characteristic optical, electronic, and catalytic properties. In this work, 5‐(2‐pyridyl)‐ and 5,10,15‐tri(2‐pyridyl)‐B^III‐subporphyrins were prepared and used to produce cyclometalated subporphyrins by reactions with [Cp*IrCl₂]₂, which proceeded through an efficient C?H activation to give the corresponding mono‐ and tri‐Ir^III complexes, respectively. While the mono‐Ir^III complex was obtained as a diastereomeric mixture, a C₃‐symmetric tri‐Ir^III complex with the three Cp*‐units all at the concave side was predominantly obtained in a high yield of 90 %, which displays weak NIR phosphorescence even at room temperature in degassed CH₂Cl₂, differently from the mono‐Ir^III complexes.     

Cooperativity as quantification and optimization paradigm for nuclear receptor modulators

Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (K^I_D) and NR–ligand binding (K^II_D), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.

A cooperativity framework describes the formation of nuclear receptor ternary complexes and deconvolutes ligand and cofactor binding into intrinsic affinities and a cooperativity factor, providing a conceptually new understanding of NR modulation.