Role of electron and hole doping in the NdNi1-xVxO3 nanostructure.

Neodymium nickelate, NdNiO3, attracts attention due to the simultaneous occurrence of several phase transitions around the same temperature. The electronic properties of NdNiO3 are extremely complex as structural distortion, electron correlation, charge ordering, and orbital overlapping play significant roles in the transitions. We report the effects of electron and hole injection via doping a single 3d metal, V, in the NdNiO3 nanostructure to understand the variations in the electronic properties without any structural distortion. A reversible resistivity modulation of more than five orders of magnitude via hole doping and complete suppression of the metal to insulator transition via electron doping is observed along with the switching of major charge carriers. The modulation of electronic properties without any structural distortion and external strain opens up new directions to consider the NdNi1-xVxO3 nanostructures applicable as emerging electronic devices.

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance.

The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. Here, we describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and a polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA) or hydroxypropyl methylcellulose acetate succinate, with or without Na+/K+ salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of a low-dosage regimen for this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.

Quantifying Functional-Group-like Structural Fragments in Molecules and Its Applications in Drug Design.

A functional group in a molecule is a structural fragment consisting of a few atoms or a single atom that imparts reactivity to a molecule. Hence, defining functional groups is crucial in chemistry to predict the properties and reactivities of molecules. However, there is no established method in the literature for defining functional groups based on reactivity parameters. In this work, we addressed this issue by designing a set of predefined structural fragments along with reactivity parameters like electron conjugation and ring strain. This approach uses bond orders and atom connectivities to quantify the presence of these fragments within an organic molecule based on a given input molecular coordinate. To assess the effectiveness of this approach, we performed a case study to show the benefits of using these newly designed structural fragments instead of traditional fingerprint-based methods for grouping potential COX1/COX2 inhibitors by screening an approved drug library against aspirin molecule. The structural fragment-based model for ternary classification of rat oral LD50 of chemicals showed performance similar to the fingerprint-based models. In evaluating the regression model performance for aqueous solubility, log(S), predictions, our approach outperformed the fingerprint-based model.

Air and water stable germacarbonyl compounds.

Germacarbonyl compounds are the germanium analogs of carbonyl compounds requiring an inert atmosphere for stability. Making these compounds survive the ambient conditions was not feasible given the lability of the Ge[double bond, length as m-dash]E bonds (E = O, S, Se, Te). However, the first examples of germacarbonyl compounds synthesized under ambient conditions by taking advantage of dipyrromethene ligand stabilization are detailed here; the isolated compounds are thiogermanone 3, selenogermanone 4, thiogermacarboxylic acid 6, selenogermacarboxylic acid 7, thiogermaester 9, selenogermaester 10, thiogermaamide 12, and selenogermaamide 13 with Ge[double bond, length as m-dash]E bonds (E = S, Se). Compounds 12 and 13 can react under atmospheric conditions with copper(i) halides offering air and water stable monomeric 14-15 and dimeric 16-19 copper(i) complexes (halide = Cl, Br, I). Apart from just binding, selectivity was also observed; thiogermaamide 12 and selenogermaamide 13 bind CuCl and CuBr, respectively, when treated with a mixture of copper(i) halides.

Cloning, expression and characterization of PURase gene from Pseudomonas sp. AKS31.

Polyurethane (PUR) is a soil and aquatic contaminant throughout the world. Towards bioremediation, in a previous study, a soil bacterium, Pseudomonas sp. AKS31, capable of efficiently degrading PUR was isolated. Polyurethanase (PURase) enzyme is capable of cleaving the ester bond of PUR and is considered as a key regulator of PUR biodegradation. Hence, for a high yield, easy purification, and further characterization, the aim of this study was to clone and overexpress the PURase gene of this isolate. The current study also investigated structural aspects of this enzyme through predictive bioinformatics analyses. In this context, the PURase gene of the isolate was cloned and expressed in E. coli using pET28(a)+ vector. The obtained recombinant protein was found insoluble. Therefore, first, the protein was made soluble with urea and purified using nickel-NTA beads. The purified enzyme exhibited substantial activities when tested on the LA-PUR plate. Bioinformatics-based analysis of the protein revealed the presence of a lipase serine active site and indicated that this PURase belongs to the Family 1.3 lipase. Hence, the present study shows that active PURase can be produced in large quantities using a prokaryotic expression system and thus, provides an effective strategy for in-vitro PUR-degradation.

Anomalous structural behavior and antiferroelectricity in BiGdO3: detailed temperature and high-pressure study.

A comprehensive temperature and high-pressure investigation on BiGdO3is carried out by means of dielectric constant, piezoelectric current, polarization-electric field loop, Raman scattering and x-ray diffraction measurements. Temperature dependent dielectric constant and dielectric loss show two anomalies at about 290 K (Tr) and 720 K (TC). The latter anomaly is most likely due to antiferroelectric to paraelectric transition as hinted by piezoelectric current and polarization-electric field loop measurements at room temperature, while the former anomaly suggests reorientation of polarization. A small deviation from linear behaviour of both the Raman modes due to structural modification in the vicinity ofTC; and sharp decrease in integrated intensities of these two modes aboveTCprovide further proof for the above antiferroelectric to paraelectric transition. Cubic to monoclinic structural transition is observed at about 10 GPa in high-pressure x-ray diffraction studies accompanied by anisotropic lattice parameter changes and large unit cell volume collapse during the transition. This structural transition is corroborated by anomalous softening and large increase in full width half maximum of M2(640 cm-1) Raman mode above 10 GPa. We speculate that enhancement of large structural distortion and large reduction inc/aratio above 10 GPa might be associated with antiferroelectric to ferroelectric transition in the system.

An electron transfer competent structural ensemble of membrane-bound cytochrome P450 1A1 and cytochrome P450 oxidoreductase.

Cytochrome P450 (CYP) heme monooxygenases require two electrons for their catalytic cycle. For mammalian microsomal CYPs, key enzymes for xenobiotic metabolism and steroidogenesis and important drug targets and biocatalysts, the electrons are transferred by NADPH-cytochrome P450 oxidoreductase (CPR). No structure of a mammalian CYP-CPR complex has been solved experimentally, hindering understanding of the determinants of electron transfer (ET), which is often rate-limiting for CYP reactions. Here, we investigated the interactions between membrane-bound CYP 1A1, an antitumor drug target, and CPR by a multiresolution computational approach. We find that upon binding to CPR, the CYP 1A1 catalytic domain becomes less embedded in the membrane and reorients, indicating that CPR may affect ligand passage to the CYP active site. Despite the constraints imposed by membrane binding, we identify several arrangements of CPR around CYP 1A1 that are compatible with ET. In the complexes, the interactions of the CPR FMN domain with the proximal side of CYP 1A1 are supplemented by more transient interactions of the CPR NADP domain with the distal side of CYP 1A1. Computed ET rates and pathways agree well with available experimental data and suggest why the CYP-CPR ET rates are low compared to those of soluble bacterial CYPs.

Isolation of a soil bacterium for remediation of polyurethane and low-density polyethylene: a promising tool towards sustainable cleanup of the environment.

A soil bacterium, designated strain AKS31, was isolated on the plastic polyurethane (PUR) and based on the molecular and biochemical analysis was tentatively assigned to the genus Pseudomonas. Preliminary studies suggested that strain AKS31 had the capability of biodegrading polyurethane (PUR) and low-density polyethylene (LDPE). This observation was confirmed by the analysis of the biodegradation products. The hydrolyzed products of PUR analyzed sequentially by High-Performance Liquid Chromatography (HPLC) and Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) showed the presence of diethylene glycol suggesting the presence of an esterase. A gene that could be involved in producing an esterase-like activity (PURase gene) was identified after the amplification and sequencing of a PCR product. Fourier Transformed Infrared (FTIR) spectrophotometric analysis of AKS31-treated LDPE film revealed the incorporation of hydroxyl groups suggesting the involvement of a hydroxylase in the degradation of LDPE. It is established that plastics form microplastics and microbeads in soils which negatively impact the health of living organisms and there have been concentrated research efforts to remediate this problem. Microcosm studies revealed that when strain AKS31 was bioaugmented with soil both the polymers were degraded during which time the heterotrophic plate counts, soil respiration and soil organic carbon content increased but this was not the case with the control nonbioaugmented microcosm. The results demonstrate that the strain AKS31 may have the potential in biodegradation of PUR and LPDE present as plastic microbeads and thereby improving soil health. Further studies in this direction are warranted. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-020-02592-9.

Edible marine algae: a new source for anti-mycobacterial agents.

Tuberculosis is a dreaded disease, which causes innumerable death worldwide. The emergence of drug resistance strains makes the situation devastating. Therefore, for better management of public health, it is mandatory to search for new anti-mycobacterial agents. In this context, the current study investigated two edible marine algae, Ulva lactuca and Ulva intestinalis, for the probable source of new anti-mycobacterial agents. To test the anti-mycobacterial activity, alcoholic extracts of these two algae were spotted on the Mycobacterium smegmatis lawn. Upon incubation, clear zone was observed at the spots. It indicated that these two extracts have anti-mycobacterial activity. In addition, their anti-biofilm property was also tested. It was found that both the extracts inhibit the mycobacterial biofilm development as well as they can disperse the preformed mycobacterial biofilm. Since these two are capable of dispersing preformed mycobacterial biofilm, it is possible that in the presence of either of these two extracts, isoniazid and rifampicin can kill biofilm encapsulated mycobacterium in combinatorial therapy. Consistent with the hypothesis, rifampicin and isoniazid killed mycobacteria that were present in biofilm. Thus, these two extracts augment the activity of rifampicin and isoniazid upon biofilm dispersal. Moreover, treatment of different cell lines with these two extracts exhibited no or little cytotoxic effects. Thus, these two agents have the potential to be good therapeutic agents against mycobacterial diseases.

The Effect of Force-Field Parameters on Cytochrome P450-Membrane Interactions: Structure and Dynamics.

The simulation of membrane proteins requires compatible protein and lipid force fields that reproduce the properties of both the protein and the lipid bilayer. Cytochrome P450 enzymes are bitopic membrane proteins with a transmembrane helical anchor and a large cytosolic globular domain that dips into the membrane. As such, they are representative and challenging examples of membrane proteins for simulations, displaying features of both peripheral and integral membrane proteins. We performed molecular dynamics simulations of three cytochrome P450 isoforms (2C9, 2C19 and 1A1) in a 2-oleoyl-1-palmitoyl-sn-glycerol-3-phosphocholine bilayer using two AMBER force field combinations: GAFF-LIPID with ff99SB for the protein, and LIPID14 with ff14SB for the protein. Comparison of the structural and dynamic properties of the proteins, the lipids and the protein-membrane interactions shows differing sensitivity of the cytochrome P450 isoforms to the choice of force field, with generally better agreement with experiment for the LIPID14 + ff14SB combination.

A Prelude to Biogermylene Chemistry*.

The biological applications of germylenes remain unrealised owing to their unstable nature. We report the isolation of air-, water-, and culture-medium-stable germylene DPMGeOH (3; DPM=dipyrromethene ligand) and its potential biological application. Compound 3 exhibits antiproliferative effects comparable to that of cisplatin in human cancer cells. The cytotoxicity of compound 3 on normal epithelial cells is minimal and is similar to that of the currently used anticancer drugs. These findings provide a framework for a plethora of biological studies using germylenes and have important implications for low-valent main-group chemistry.

RASPD+: Fast Protein-Ligand Binding Free Energy Prediction Using Simplified Physicochemical Features.

The virtual screening of large numbers of compounds against target protein binding sites has become an integral component of drug discovery workflows. This screening is often done by computationally docking ligands into a protein binding site of interest, but this has the drawback of a large number of poses that must be evaluated to obtain accurate estimates of protein-ligand binding affinity. We here introduce a fast pre-filtering method for ligand prioritization that is based on a set of machine learning models and uses simple pose-invariant physicochemical descriptors of the ligands and the protein binding pocket. Our method, Rapid Screening with Physicochemical Descriptors + machine learning (RASPD+), is trained on PDBbind data and achieves a regression performance that is better than that of the original RASPD method and traditional scoring functions on a range of different test sets without the need for generating ligand poses. Additionally, we use RASPD+ to identify molecular features important for binding affinity and assess the ability of RASPD+ to enrich active molecules from decoys.

Mechanically interlocked architecture aids an ultra-stiff and ultra-hard elastically bendable cocrystal.

Molecular crystals are not known to be as stiff as metals, composites and ceramics. Here we report an exceptional mechanical stiffness and high hardness in a known elastically bendable organic cocrystal [caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB) and methanol (1:1:1)] which is comparable to certain low-density metals. Spatially resolved atomic level studies reveal that the mechanically interlocked weak hydrogen bond networks which are separated by dispersive interactions give rise to these mechanical properties. Upon bending, the crystals significantly conserve the overall energy by efficient redistribution of stress while perturbations in hydrogen bonds are compensated by strengthened π-stacking. Furthermore we report a remarkable stiffening and hardening in the elastically bent crystal. Hence, mechanically interlocked architectures provide an unexplored route to reach new mechanical limits and adaptability in organic crystals. This proof of concept inspires the design of light-weight, stiff crystalline organics with potential to rival certain inorganics, which currently seem inconceivable.

Donor-acceptor-stabilised germanium analogues of acid chloride, ester, and acyl pyrrole compounds: synthesis and reactivity.

Germaacid chloride, germaester, and N-germaacyl pyrrole compounds were not known previously. Therefore, donor-acceptor-stabilised germaacid chloride (i-Bu)2ATIGe(O)(Cl) → B(C6F5)3 (1), germaester (i-Bu)2ATIGe(O)(OSiPh3) → B(C6F5)3 (2), and N-germaacyl pyrrole (i-Bu)2ATIGe(O)(NC4H4) → B(C6F5)3 (3) compounds, with Cl-Ge[double bond, length as m-dash]O, Ph3SiO-Ge[double bond, length as m-dash]O, and C4H4N-Ge[double bond, length as m-dash]O moieties, respectively, are reported here. Germaacid chloride 1 reacts with PhCCLi, KOt-Bu, and RLi (R = Ph, Me) to afford donor-acceptor-stabilised germaynone (i-Bu)2ATIGe(O)(CCPh) → B(C6F5)3 (4), germaester (i-Bu)2ATIGe(O)(Ot-Bu) → B(C6F5)3 (5), and germanone (i-Bu)2ATIGe(O)(R) → B(C6F5)3 (R = Ph 6, Me 7) compounds, respectively. Interconversion between a germaester and a germaacid chloride is achieved; reaction of germaesters 2 and 5 with TMSCl gave germaacid chloride 1, and 1 reacted with Ph3SiOLi and KOt-Bu to produce germaesters 2 and 5. Reaction of N-germaacyl pyrrole 3 with thiophenol produced a donor-acceptor-stabilised germaacyl thioester (i-Bu)2ATIGe(O)(SPh) → B(C6F5)3 (10). Furthermore, the attempted syntheses of germaamides and germacarboxylic acids are also discussed.

Pressure induced anomalous magnetic behaviour in nanocrystalline YCrO3 at room temperature.

High pressure behaviour of nanocrystalline YCrO3 is investigated up to 10 GPa using electrical, magnetic, synchrotron x-ray diffraction and Raman spectroscopy measurements. High pressure dielectric constant measurements show a sharp peak at 4.5 GPa, though the sample is found to be in ferroelectric phase up to the highest pressure of our study from piezoelectric current measurements. X-ray diffraction measurements show absence of any structural phase transition, however anomalies are observed in the unit cell structural parameters at about 4.3 GPa and the Y-atom position shows a maximum shift at the same pressure. In the absence of any structural transition, anomalous behaviour of relevant Raman modes with minimum in the Raman band width at about same pressure indicate towards a spin-phonon interaction. AC magnetic measurements in the toroid anvil cell show an anomalous enhancement of magnetic moment above 4 GPa indicating a collective magnetic response of nanoparticles.

Pseudohalogenogermylenes versus Halogenogermylenes: Difference in their Complexation Behavior towards Group 6 Metal Carbonyls.

Pseudohalogenogermylenes [(iBu)2 ATI]GeY (Y=NCO 4, NCS 5) show different coordination behavior towards group 6 metal carbonyls in comparison to the corresponding halogenogermylenes [(iBu)2 ATI]GeX (X=F 1, Cl 2, Br 3) (ATI=aminotroponiminate). The reactions of compounds 4-5 and 1-3 with cis-[M(CO)4 (COD)] (M=Mo, W, COD=cyclooctadiene) gave trans-germylene metal complexes {[(iBu)2 ATI]GeY}2 M(CO)4 (Y=NCO, M=Mo 6, W 11; Y=NCS, M=Mo 7) and cis-germylene metal complexes {[(iBu)2 ATI]GeX}2 M(CO)4 (M=Mo, X=F 8, Cl 9, Br 10; M=W, X=Cl 12), respectively. Theoretical studies on compounds 7 and 9 reveal that donor-acceptor interactions from Mo to Ge atoms are better stabilized in the observed trans and cis geometries than in the hypothetical cis and trans structures, respectively.

Mechanism of the formation of the RecA-ssDNA nucleoprotein filament structure: a coarse-grained approach.

In prokaryotes, the RecA protein catalyzes the repair and strand exchange of double-stranded DNA. RecA binds to single-stranded DNA (ssDNA) and forms a presynaptic complex in which the protein polymerizes around the ssDNA to form a right-handed helical nucleoprotein filament structure. In the present work, the mechanism for the formation of the RecA-ssDNA filament structure is modeled using coarse-grained molecular dynamics simulations. Information from the X-ray structure was used to model the protein itself but not its interactions; the interactions between the protein and the ssDNA were modeled solely by electrostatic, aromatic, and repulsive energies. For the present study, the monomeric, dimeric, and trimeric units of RecA and 4, 8, and 11 NT-long ssDNA, respectively, were studied. Our results indicate that monomeric RecA is not sufficient for nucleoprotein filament formation; rather, dimeric RecA is the elementary binding unit, with higher multimeric units of RecA facilitating filament formation. Our results reveal that loop region flexibility at the primary binding site of RecA is essential for it to bind the incoming ssDNA, that the aromatic residues present in the loop region play an important role in ssDNA binding, and that ATP may play a role in guiding the ssDNA by changing the electrostatic potential of the RecA protein.

A cationic aluminium complex: an efficient mononuclear main-group catalyst for the cyanosilylation of carbonyl compounds.

A structurally characterized cationic aluminium complex [(AT)Al(DMAP)]+[OTf]- (3) stabilized through a relatively nonbulky aminotroponate (AT) ligand is reported (DMAP = 4-(dimethylamino)pyridine). This compound was found to work as an excellent mononuclear main-group catalyst of the cyanosilylation of a variety of aldehydes and ketones. Loadings of 1 to 2 mol% of this catalyst consumed these substrates in just 5 to 30 min at room temperature.

High Pressure Experimental Studies on CuO: Indication of Re-entrant Multiferroicity at Room Temperature.

We have carried out detailed experimental investigations on polycrystalline CuO using dielectric constant, dc resistance, Raman spectroscopy and X-ray diffraction measurements at high pressures. Observation of anomalous changes both in dielectric constant and dielectric loss in the pressure range 3.7-4.4 GPa and reversal of piezoelectric current with reversal of poling field direction indicate to a change in ferroelectric order in CuO at high pressures. A sudden jump in Raman integrated intensity of Ag mode at 3.4 GPa and observation of Curie-Weiss type behaviour in dielectric constant below 3.7 GPa lends credibility to above ferroelectric transition. A slope change in the linear behaviour of the Ag mode and a minimum in the FWHM of the same indicate indirectly to a change in magnetic ordering. Since all the previous studies show a strong spin-lattice interaction in CuO, observed change in ferroic behaviour at high pressures can be related to a reentrant multiferroic ordering in the range 3.4 to 4.4 GPa, much earlier than predicted by theoretical studies. We argue that enhancement of spin frustration due to anisotropic compression that leads to change in internal lattice strain brings the multiferroic ordering to room temperature at high pressures.