Taking a different road: following Ag25 and Au25 cluster activation via in situ differential pair distribution function analysis.

Synchrotron X-ray total scattering measurements and accompanying pair distribution function (PDF) analyses are an excellent characterization technique to complement both transmission electron microscopy (TEM) and extended X-ray absorption fine structure (EXAFS) spectroscopy methods for detailed structural studies of atom-precise metal clusters. Herein, we study the thermal activation of Au25(SR)18- and Ag25(SR)18- clusters on alumina supports via in situ differential PDF (dPDF) analyses to compare structural changes in the metal clusters upon thermal activation in air. The metal-metal interatomic distances in Au25(SR)18- and Ag25(SR)18- clusters as measured by the dPDF method are comparable with those measured via single-crystal crystallographic and EXAFS methods. Compared to EXAFS analysis, in situ dPDF data can also provide high-temperature, non-element specific, longer range structural information with excellent temporal resolution. TEM and dPDF results show that Ag25(SR)18 systems behave significantly differently than analogous Au25(SR)18 systems upon thermal activation. Atom-precise Au clusters on alumina supports show continuous growth in particle size with increasing activation temperature due to particle coalescence upon thermal deprotection, and grow to an average size of 11.2 ± 2.1 nm for samples thermally activated at 650 °C. Conversely, analogous Ag clusters on alumina supports show particle size growth to mid-sized particles (3.2 ± 0.4 nm) at activation temperatures of 450 °C, beyond which the Ag particles then undergo thermal degradation to give smaller Ag clusters with an average size of 1.4 ± 0.2 nm for samples thermally activated at 650 °C. The significant difference in the behaviours of atom-precise, thiolate-protected Au and Ag clusters upon thermal activation emphasizes the development of distinct activation protocols for different metal cluster systems.

Exploring the structure of atom-precise silver-palladium bimetallic clusters prepared via improved single-pot co-reduction synthesis protocol.

Designing atom-precise bimetallic clusters with a relatively cost-effective and more abundant metal than Au (i.e., Ag) is desirable for the development of heterogeneous bimetallic cluster catalysts for industrial applications. Atom-precise Ag-based bimetallic clusters, which are analogs of the well-studied Au based clusters, are yet to be fully explored as catalysts. Establishing the Pd loading limit and the position of the Pd dopant in AgPd bimetallic clusters will further give an insight into the structure-activity relationships for these atom-precise AgPd heterogeneous catalysts. In this study, an improved single-pot co-reduction strategy was employed to prepare the bimetallic clusters, which were then characterized by mass spectrometry, x-ray photoelectron spectroscopy (XPS), and x-ray absorption spectroscopy (XAS) to identify the loading and position of the dopant metal. Our results show that only a single dopant Pd atom can be incorporated, and in comparison with monometallic Ag25 clusters, the absorption peaks of Ag24Pd1(SPhMe2)18 2- bimetallic clusters are blue shifted due to the incorporation of Pd. The XPS and XAS results show that the Ag24Pd1(SPhMe2)18 2- bimetallic clusters have multivalent Ag(0) and Ag(I) atoms and surprisingly show Pd(II) species with significant Pd-S bonding, despite the prevailing wisdom that the Pd dopant should be in the center of the cluster. The XAS results show that the singly doped Pd atom predominantly occupies the staple position, albeit we cannot unambiguously rule out the Pd atom in an icosahedral surface position in some clusters. We discuss the ramifications of these results in terms of possible kinetically vs thermodynamically controlled cluster formation.

Activation of atom-precise clusters for catalysis.

The use of atom-precise, ligand-protected metal clusters has exceptional promise towards the fabrication of model supported-nanoparticle heterogeneous catalysts which have controlled sizes and compositions. One major challenge in the field involves the ease at which metallic clusters sinter upon removal of protected ligands, thus destroying the structural integrity of the model system. This review focuses on methods used to activate atom-precise thiolate-stabilized clusters for heterogeneous catalysis, and strategies that can be used to mitigate sintering. Thermal activation is the most commonly employed approach to activate atom-precise metal clusters, though a variety of chemical and photochemical activation strategies have also been reported. Material chemistry methods that can mitigate sintering are also explored, which include overcoating of clusters with metal oxide supports fabricated by sol-gel chemistry or atomic layer deposition of thin oxide films or encapsulating clusters within porous supports. In addition to focusing on the preservation of the size and morphology of deprotected metal clusters, the fate of the removed ligands is also explored, because detached and/or oxidized ligands can also greatly influence the overall properties of the catalyst systems. We also show that modern characterization techniques such as X-ray absorption spectroscopy and high-resolution electron microscopy have the capacity to enable careful monitoring of particle sintering upon activation of metal clusters.

COVID-19: CADD to the rescue.

The recent outbreak of the deadly COVID-19 disease, being caused by the novel coronavirus (SARS-CoV-2), has put the world on red alert as it keeps spreading and recording more fatalities. Research efforts are being carried out to curtail the disease from spreading as it has been declared as of global health emergency. Hence, there is an exigent need to identify and design drugs that are capable of curing the infection and hinder its continual spread across the globe. Herein, a computer-aided drug design tool known as the virtual screening method was used to screen a database of 44 million compounds to find compounds that have the potential to inhibit the surface glycoprotein responsible for virus entry and binding. The consensus scoring approach selected three compounds with promising physicochemical properties and favorable molecular interactions with the target protein. These selected compounds can undergo lead optimization to be further developed as drugs that can be used in treating the COVID-19 disease.

Activation of atomically precise silver clusters on carbon supports for styrene oxidation reactions.

Metal clusters have distinct features such as large surface area, low-coordination-atom enriched surfaces, and discrete energy levels that influence their behavior during catalytic reactions. Atomically-precise Ag clusters, which are analogues of more well-studied Au clusters, are yet to be fully explored as catalysts for various chemical reactions. 2,4-Dimethylbenzenethiol-protected Ag25 clusters were prepared and deposited onto carbon supports followed by calcination. Results from X-ray absorption fine structure (EXAFS) spectroscopy measurements and other characterization techniques indicated that thermal activation of carbon-supported Ag25 clusters resulted in dethiolation of Ag clusters at 250 °C and beyond, and consequently mild growth in particle sizes of Ag clusters on carbon supports was seen with increasing activation temperatures. Both as-prepared and activated Ag25 clusters were active for styrene oxidation reactions, with high selectivity towards styrene oxide, without using any promoter. Results show that mild activation at 250 °C yields the most active catalysts, and higher activation temperatures lead to decreased activities and slightly poorer selectivity to styrene oxidation as a result of cluster sintering. EXAFS data shows the resulting activated clusters are composed of Ag metal and that all thiols are removed from the Ag cluster surfaces, though XPS data shows that thiol oxidation products are still present in the sample.

Molecular dynamics and combined docking studies for the identification of Zaire ebola virus inhibitors.

Ebola virus (EBOV) is a lethal human pathogen with a risk of global spread of its zoonotic infections, and Ebolavirus Zaire specifically has the highest fatality rate amongst other species. There is a need for continuous effort towards having therapies, as a single licensed treatment to neutralize the EBOV is yet to come into reality. This present study virtually screened the MCULE database containing almost 36 million compounds against the structure of a Zaire Ebola viral protein (VP) 35 and a consensus scoring of both MCULE and CLCDDW docking programs remarked five compounds as potential hits. These compounds, with binding energies ranging from -7.9 to -8.9 kcal/mol, were assessed for predictions of their physicochemical and bioactivity properties, as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The results of the 50 ns molecular dynamics simulations showed the presence of dynamic stability between ligand and protein complexes, and the structures remained significantly unchanged at the ligand-binding site throughout the simulation period. Both docking analysis and molecular dynamics simulation studies suggested strong binding affinity towards the receptor cavity and these selected compounds as potential inhibitors against the Zaire Ebola VP 35. With respect to inhibition constant values, bioavailability radar and other physicochemical properties, compound A (MCULE-1018045960-0-1) appeared to be the most promising hit compound. However, the ligand efficiency and ligand efficiency scale need improvement during optimization, and also validation via in vitro and in vivo studies are necessary to finally make a lead compound in treating Ebola virus diseases. Communicated by Ramaswamy H. Sarma.

Structure based virtual screening of the Ebola virus trimeric glycoprotein using consensus scoring.

Ebola virus (EBOV) causes zoonotic viral infection with a potential risk of global spread and a highly fatal effect on humans. Till date, no drug has gotten market approval for the treatment of Ebola virus disease (EVD), and this perhaps allows the use of both experimental and computational approaches in the antiviral drug discovery process. The main target of potential vaccines that are recently undergoing clinical trials is trimeric glycoprotein (GP) of the EBOV and its exact crystal structure was used in this structure based virtual screening study, with the aid of consensus scoring to select three possible hit compounds from about 36 million compounds in MCULE's database. Amongst these three compounds, (5R)-5-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]-N-[(4-methoxyphenyl)methyl]-4,5-dihydroisoxazole-3-carboxamide (SC-2, C21H19ClN4O4) showed good features with respect to drug likeness, ligand efficiency metrics, solubility, absorption and distribution properties and non-carcinogenicity to emerge as the most promising compound that can be optimized to lead compound against the GP EBOV. The binding mode showed that SC-2 is well embedded within the trimeric chains of the GP EBOV with molecular interactions with some amino acids. The SC-2 hit compound, upon its optimization to lead, might be a good potential candidate with efficacy against the EBOV pathogen and subsequently receive necessary approval to be used as antiviral drug for the treatment of EVD.

Predicting of the refractive index of haemoglobin using the Hybrid GA-SVR approach.

The optical properties of blood play crucial roles in medical diagnostics and treatment, and in the design of new medical devices. Haemoglobin is a vital constituent of the blood whose optical properties affect all of the optical properties of human blood. The refractive index of haemoglobin has been reported to strongly depend on its concentration which is a function of the physiology of biological cells. This makes the refractive index of haemoglobin an essential non-invasive bio-marker of diseases. Unfortunately, the complexity of blood tissue makes it challenging to experimentally measure the refractive index of haemoglobin. While a few studies have reported on the refractive index of haemoglobin, there is no solid consensus with the data obtained due to different measuring instruments and the conditions of the experiments. Moreover, obtaining the refractive index via an experimental approach is quite laborious. In this work, an accurate, fast and relatively convenient strategy to estimate the refractive index of haemoglobin is reported. Thus, the GA-SVR model is presented for the prediction of the refractive index of haemoglobin using wavelength, temperature, and the concentration of haemoglobin as descriptors. The model developed is characterised by an excellent accuracy and very low error estimates. The correlation coefficients obtained in these studies are 99.94% and 99.91% for the training and testing results, respectively. In addition, the result shows an almost perfect match with the experimental data and also demonstrates significant improvement over a recent mathematical model available in the literature. The GA-SVR model predictions also give insights into the influence of concentration, wavelength, and temperature on the RI measurement values. The model outcome can be used not only to accurately estimate the refractive index of haemoglobin but also could provide a reliable common ground to benchmark the experimental refractive index results.

Identification of potential inhibitors against the Zika virus using consensus scoring.

The Zika virus (ZIKV) is a life threatening pathogen of zoonotic importance with prevalence in some parts of Africa and America. Unfortunately, there is yet to be a single approved vaccine or antiviral drug to treat the diseases and deformations being caused by the Zika virus infection. In this study, about 36 million compounds from MCULE database were virtually screened against a real matured ZIKV protein using a consensus scoring method to get improved hit rates. The consensus scoring method combined the result from the 25 top ranked molecules from both MCULE and Drug Score eXtended (DSX) docking programs which led to the selection of two hit compounds. The inhibition constant (Ki) values of 0.08 and 0.30µm were obtained for the two selected compounds MCULE-8830369631-0-1 and MCULE-9236850811-0-1 respectively, to remark them as hit compounds. The molecular interactions of the two selected hit compounds with the amino acids (ALA 48, ILE 49, ILE 468 and LEU 472) present in the ZIKV protein indicated that they both have similar binding modes. The result of the computationally predicted physicochemical properties including ADMET for the selected compounds showed their great potential in becoming lead compounds upon optimization and thus could be used in treating the Zika virus diseases.