Unveiling Adenine H‑bonded Hexads: Hierarchical Self-Assembly for Helical Columnar Functional Materials.

This manuscript reports on an unusual self-assembly of small adenine-based molecules leading to complex, functional systems. Molecules feature an adenine nucleobase substituted at the N9 position with a triarylamine unit through a flexible spacer. Hydrogen bonding interactions prompt the formation of unprecedented adenine hexameric rosettes, which organize in dimers and then into helical columnar assemblies exhibiting hexagonal columnar liquid crystal phases, even with nonchiral molecules.

Oleuropein Aglycone, an Olive Polyphenol, Influences Alpha-Synuclein Aggregation and Exerts Neuroprotective Effects in Different Parkinson's Disease Models.

Α-synuclein aggregation is the pathological feature of several neurodegenerative disorders, including Parkinson's disease. The aggregates can diffuse within brain areas, and their toxicity has been proven in both cellular and animal models. Given that, recent therapeutic strategies have been focusing on the identification of compounds able to promote the degradation of aggregates or, at least, to prevent the aggregation process.

Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 M Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation.

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (M) using DCM compounds as ligands.

The Discovery of inhibitors of the SARS-CoV-2 S protein through computational drug repurposing.

SARS-CoV-2 must bind its principal receptor, ACE2, on the target cell to initiate infection. This interaction is largely driven by the receptor binding domain (RBD) of the viral Spike (S) protein. Accordingly, antiviral compounds that can block RBD/ACE2 interactions can constitute promising antiviral agents.

Tyrosol: Repercussion of the Lack of a Hydroxyl-Group in the Response of MCF-7 Cells to Hypoxia.

In solid tumors, such as breast cancer, hypoxic microenvironment worsens patient prognoses. We have previously reported in MCF-7 breast cancer cells that, under hypoxic conditions, hydroxytyrosol (HT) downregulates the level of reactive oxygen species, reduces the expression of hypoxia inducible factor-1 (HIF-1), and, at high concentrations, can bind to the aryl hydrocarbon receptor (AhR). With this background, the present study investigated whether the most abundant extra virgin olive oil (EVOO) phenolic compound tyrosol (TYR), with a chemical structure similar to HT but with only one hydroxyl group, exerts comparable effects.

Autochthonous Peruvian Natural Plants as Potential SARS-CoV-2 M Main Protease Inhibitors.

Over 750 million cases of COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been reported since the onset of the global outbreak. The need for effective treatments has spurred intensive research for therapeutic agents based on pharmaceutical repositioning or natural products. In light of prior studies asserting the bioactivity of natural compounds of the autochthonous Peruvian flora, the present study focuses on the identification SARS-CoV-2 M main protease dimer inhibitors.

Shedding light on the binding mechanism of kinase inhibitors BI-2536, Volasetib and Ro-3280 with their pharmacological target PLK1.

In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain.

Discovery of Diverse Natural Products as Inhibitors of SARS-CoV-2 M Protease through Virtual Screening.

SARS-CoV-2 is a type of coronavirus responsible for the international outbreak of respiratory illness termed COVID-19 that forced the World Health Organization to declare a pandemic infectious disease situation of international concern at the beginning of 2020. The need for a swift response against COVID-19 prompted to consider different sources to identify bioactive compounds that can be used as therapeutic agents, including available drugs and natural products. Accordingly, this work reports the results of a virtual screening process aimed at identifying antiviral natural product inhibitors of the SARS-CoV-2 M viral protease.

Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites.

Diverse computational methods to support fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy in supporting FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not yet been clearly overcome in the framework of biomolecular simulations. In the present work, we discuss a systematic semi-automatic novel computational procedure, designed to surpass these difficulties.

Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides.

Apoptosis is a key cell death pathway in mammalian cells. Understanding this process and its regulation has been a subject of study in the last three decades. Members of the Bcl-2 family of proteins are involved in the regulation of apoptosis through mitochondrial poration with the subsequent initiation of apoptosis.

Toward understanding calmodulin plasticity by molecular dynamics.

Calmodulin interacts in many different ways with its ligands. We aim to shed light on its plasticity analyzing the changes followed by the linker region and the relative position of the lobes using conventional molecular dynamics, accelerated MD and scaled MD (sMD). Three different structures of calmodulin are compared, obtaining a total of 2.

Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors.

Hit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking-MM/PBSA-AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules).

Inspecting the Electronic Architecture and Semiconducting Properties of a Rosette-Like Supramolecular Columnar Liquid Crystal.

Computational and experimental studies unravel the structural and electronic properties of a novel supramolecular liquid crystal built through a hierarchical assembly process resulting in an H-bonded melamine rosette decorated with peripheral triphenylenes. The six-fold symmetry of the mesogen facilitates the formation of a highly organized hexagonal columnar mesophase stable at room temperature. X-ray diffraction and electron density maps confirm additional intra- and intercolumn segregation of functional subunits, and this paves the way for 1D charge transport.

A multistep docking and scoring protocol for congeneric series: Implementation on kinase DFG-out type II inhibitors.

Aim: Rescoring of docking-binding poses can significantly improve molecular docking results. Our aim was to evaluate postprocessing docking protocols in order to determine the most suitable methodology for the study of the binding of congeneric compounds to protein kinases.

Materials & Methods: Diverse ligand-receptor poses generated after docking were submitted to different relaxation protocols.

Binding of the anticancer drug BI-2536 to human serum albumin. A spectroscopic and theoretical study.

BI-2536 is a potent Polo-like kinase inhibitor which induces apoptosis in diverse human cancer cell lines. The binding affinity of BI-2536 for human serum albumin (HSA) protein may define its pharmacokinetic and pharmacodynamic profile. We have studied the binding of BI-2536 to HSA by means of different spectroscopic techniques and docking calculations.

Effect of five-membered ring and heteroatom substitution on charge transport properties of perylene discotic derivatives: A theoretical approach.

Density functional theory calculations were carried out to investigate the evolvement of charge transport properties of a set of new discotic systems as a function of ring and heteroatom (B, Si, S, and Se) substitution on the basic structure of perylene. The replacement of six-membered rings by five-membered rings in the reference compound has shown a prominent effect on the electron reorganization energy that decreases ∼0.2 eV from perylene to the new carbon five-membered ring derivative.

DFT study of the effect of fluorine atoms on the crystal structure and semiconducting properties of poly(arylene-ethynylene) derivatives.

The effect of fluorine substitution on the molecular structure, crystal packing, and n-type semiconducting properties of a set of poly(arylene-ethynylene) polymers based on alternating thiadiazole and phenyl units linked through ethynylene groups has been studied by means of Density Functional Theory. As a result, an enlargement in the interplanar distance between cofacial polymer chains, as well as a decrease of the electronic coupling and electron mobility is predicted. On the other hand, fluorination could facilitate electron injection into the material.

Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations.

B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution of valine for glutamic acid at position 600 ((V600E)B-Raf) is the most frequent. Treatment of these patients with B-Raf inhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have been identified and new potent and selective inhibitors are currently needed.

Theoretical estimation of the optical bandgap in a series of poly(aryl-ethynylene)s: a DFT study.

Aimed to optimize the ratio accuracy/computational cost, in this work we study the performance of three different theoretical methodologies in the calculation of the optical bandgap for a test set made of a number of poly(aryl-ethynylene)s related polymers. Infinite, ideal polymer chains were first optimized by means of periodic calculations. Different length oligomers were afterward generated by direct replication of the corresponding periodic structure and their optical bandgaps were calculated by means of different time dependent-density functional theory (TD-DFT) methodologies.

A DFT approach to the charge transport related properties in columnar stacked π-conjugated N-heterocycle cores including electron donor and acceptor units.

We present a density functional theory (DFT) study on charge-transport related properties in a series of discotic systems based on 1,3,5-triazine and tris[1,2,4]triazolo[1,3,5]triazine central cores as electron acceptor units, and phenyl-thiophene and N-carbazolyl-thiophene segments as electron donor units. The presence of both electron donor and acceptor moieties in the π-conjugated core could lead to new discotic liquid crystal (DLC) materials which are predicted to display ambipolar charge transport behavior in such a way that electrons could move through the central part of the next cores while holes mainly do through the peripheral groups. A significant increase in hole mobility when N-carbazolyl is present as an electron donor unit in the peripheral region is predicted.

A Tuned LRC-DFT Design of Ambipolar Diketopyrrolopyrrole-Containing Quinoidal Molecules Interesting for Molecular Electronics.

This work presents a Density Functional Theory (DFT) study on the charge transport related properties of two quinoidal diketopyrrolopyrrole (DPP) based systems. System A, recently synthesized, shows high efficiency as n-type organic semiconductor material while system B, not synthesized yet, has a linking benzothiadiazole (BT) unit between DPP moieties and would display an ambipolar character. The use of tuned, long-range corrected (LRC) functionals allows one to predict HOMO, LUMO, and charge transport properties for compound A in concordance with those experimentally observed.

Crystal structure and charge transport properties of poly(arylene-ethynylene) derivatives: a DFT approach.

In the present study, a series of crystalline poly(arylene-ethynylene) copolymers containing phenylethynylene and 2,5-dialkoxy-phenylethynylene units together with 1,3,4-thiadiazole rings has been modeled by means of periodic calculations. Optimized three-dimensional polymeric structures show interchain distances that are consistent with the experimental values reported for a related polymer. It has also been observed that the presence of pendant alkoxy chains brings on both a further flattening and a separation of the coplanar chains.

Density functional theory study of the optical and electronic properties of oligomers based on phenyl-ethynyl units linked to triazole, thiadiazole, and oxadiazole rings to be used in molecular electronics.

In the present work, we have studied from a theoretical perspective the geometry and electronic properties of the series of related compounds 2,5-bis(phenylethynyl)-1,3,4-thiadiazole, 2,5-bis(phenylethynyl)-1,3,4-oxadiazole, and 2,5-bis(phenylethynyl)-1,2,4-triazole as candidates for electron-conducting polymers and compounds with desirable (opto)electronic properties. The effect of the ethynyl group (-C[Triple Bond]C-) on the structure and electronic properties was also studied. The influence of planarity on electrical conductivity has been studied by a natural-bond-orbital analysis.

Theoretical study of the effect of ethynyl group on the structure and electrical properties of phenyl-thiadiazole systems as precursors of electron-conducting materials.

2,5-Bis(phenylethynyl)-1,3,4-thiadiazole (PhEtTh) and 2,5-diphenyl-1,3,4-thiadiazole (PhTh) are expected to be building blocks for polymer materials that could be employed to conduct electricity due to their narrow highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gaps. In this work, a theoretical, comparative study about the effect of the ethynyl group on the planarity and electrical conductivity of this kind of systems has been carried out. Thus, several ab initio (Hartree-Fock, Moller-Plesset) and DFT (B3LYP, B3PW91, M05, M05-2X) methods and basis sets (6-31G(*), 6-31G+G(**), 6-311G(**), cc-pVDZ, cc-pVTZ) have been tested.