Key Physicochemical Properties Research Articles

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches.

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature.

Study of Performance, Emissions, and Combustion of a Common-Rail Injection Engine Fuelled with Blends of Cocos nucifera Biodiesel with Diesel Oil

Renewable alternatives to fossil fuels, such as biodiesel, are necessary to lessen emission of greenhouse gases that are causing climate change. Using a high-pressure, medium-duty, common-rail, turbocharged four-cylinder diesel engine, this work studies the effect of adding Cocos nucifera biodiesel to conventional diesel on exhaust emissions, engine performance, and combustion characteristics. An analysis and characterization of the key physicochemical properties of diesel, biodiesel, and biodiesel–diesel blends were carried out. The engine was fuelled with pure petroleum diesel and blended diesel containing a 10%, 20%, 30%, and 50% volume of coconut oil at full throttle and six different speed settings, respectively. The results showed relatively close physicochemical properties between the biodiesel blend and conventional petroleum fuel. Observations made over the entire speed range indicated that a higher coconut oil biodiesel (COB) content lowers the torque and brake power compared to diesel. In the case of engine exhaust gas, a reduction in carbon monoxide (CO) and smoke emissions were observed. Notably, COB50 gives out the highest nitrogen oxides (NOx) but it is raised even for other blends. The experimental results also demonstrated that a higher COB content achieves a lower peak pressure while the peak heat release rate (PHRR) was lower than that of conventional diesel as the speed of the engine increases.

Land use effects on soil phosphorus behavior characteristics in the eutrophic aquatic-terrestrial ecotone of Dianchi Lake, China

Growing evidence suggests that land use has widespread effects on soil phosphorus (P) cycling, which can contribute to plant growth and environmental impacts. P pool and P behavior characteristics have identified as potential indicators of soil nutrient cycling and functions. In this study, we investigated effects of different land-use types (farmland and ecological buffer zone) on soil P fractions (i.e., labile P, moderately labile P, organic P, apatite P, and residual P) and soil P sorption-release characteristics at three sampling sites in the eutrophic aquatic-terrestrial ecotone of Dianchi Lake, China. In addition, we also identified key soil physicochemical properties that were significantly related to soil P fractions and sorption-release characteristics. Different land use induced changes in soil P fractions and P stocks. Organic P pool showed a significant difference between FL and BZ in all sites and other P pools displayed the site-specific responses. Soils in buffer zone have higher P buffer capacity (higher maximum sorption capacity and lower degree of P saturation) in comparison with farmland. Moreover, soil buffer capacity was significantly correlated with soil labile P. These results suggest buffer zone in lakeside may act as sink of P in reducing soil P loss. However, higher labile P and very low C: Po ratios (<100) in all soil samples indicate there is large amount of available P accumulated in soils and soil P loss risk in the aquatic-terrestrial ecotone is still high. Redundancy analysis results showed that the soil key physicochemical properties (soil organic carbon, total nitrogen, exchangeable Fe and Al concentration, and pH) were closely related to soil P fractions and sorption-release characteristics. Therefore, we conclude that soil P fractions (especially labile P, organic P) and key soil physicochemical indices are useful indicators for assessing the behavior of P in soils induced by different land use in the eutrophic aquatic-terrestrial ecotone of lakes.

Key Physicochemical Properties Dictating Gastrointestinal Bioaccessibility of Microplastics-Associated Organic Xenobiotics: Insights from a Deep Learning Approach.

A potential risk from human uptake of microplastics is the release of plastics-associated xenobiotics, but the key physicochemical properties of microplastics controlling this process are elusive. Here, we show that the gastrointestinal bioaccessibility, assessed using an in vitro digestive model, of two model xenobiotics (pyrene, at 391-624 mg/kg, and 4-nonylphenol, at 3054-8117 mg/kg) bound to 18 microplastics (including pristine polystyrene, polyvinyl chloride, polyethylene terephthalate, polypropylene, thermoplastic polyurethane, and polyethylene, and two artificially aged samples of each polymer) covered wide ranges: 16.1-77.4% and 26.4-83.8%, respectively. Sorption/desorption experiments conducted in simulated gastric fluid indicated that structural rigidity of polymers was an important factor controlling bioaccessibility of the nonpolar, nonionic pyrene, likely by inducing physical entrapment of pyrene in porous domains, whereas polarity of microplastics controlled bioaccessibility of 4-nonylphenol, by regulating polar interactions. The changes of bioaccessibility induced by microplastics aging corroborated the important roles of polymeric structures and surface polarity in dictating sorption affinity and degree of desorption hysteresis, and consequently, gastrointestinal bioaccessibility. Variance-based global sensitivity analysis using a deep learning neural network approach further revealed that micropore volume was the most important microplastics property controlling bioaccessibility of pyrene, whereas the O/C ratio played a key role in dictating the bioaccessibility of 4-nonylphenol in the gastric tract.

Alexandrian Laurel for Biodiesel Production and its Biodiesel Blends on Performance, Emission and Combustion Characteristics in Common-Rail Diesel Engine

A two-step transesterification process was employed in the biodiesel production from non-edible Alexandrian Laurel. The key physicochemical properties of the Alexandrian Laurel biodiesel (ALB), diesel and blends of both fuels were compared and analyzed. The effects of blending biodiesel (ALB) and petroleum diesel on engine performance, combustion and exhaust emissions were investigated in a turbocharged, high-pressure common-rail diesel engine under six different speed operations and at full load conditions. The test fuels comprised a conventional diesel fuel and four different fuel blends of ALB. The results showed relatively close physicochemical properties of ALB and its blends when compared with petroleum diesel. However, the use of ALB-blended fuel resulted in penalties engine brake power, brake specific fuel consumption (BSFC) despite slightly improved brake thermal efficiency (BTE). Brake specific nitrogen oxide (BSNOx) was found worsened with higher ALB content in the blends. Nonetheless, consistent improvements in brake specific carbon monoxide (BSCO), brake specific carbon dioxide (BSCO2), and smoke were noticed when ALB blends were used. Additionally, ALB blends contributed to reduction in peak combustion pressure, peak heat release rate (HRR) and combustion duration. In general, the findings suggest satisfactory operation with ALB biodiesel-diesel blends in an unmodified diesel engine.

Impact of the Physicochemical Features of TiO2 Nanoparticles on Their In Vitro Toxicity.

The concern about titanium dioxide nanoparticles (TiO2-NPs) toxicity and their possible harmful effects on human health has increased. Their biological impact is related to some key physicochemical properties, that is, particle size, charge, crystallinity, shape, and agglomeration state. However, the understanding of the influence of such features on TiO2-NP toxicity remains quite limited. In this study, cytotoxicity, proinflammatory response, and oxidative stress caused by five types of TiO2-NPs with different physicochemical properties were investigated on A549 cells used either as monoculture or in co-culture with macrophages differentiated from the human monocytic THP-1 cells. We tailored bulk and surface TiO2 physicochemical properties and differentiated NPs for size/specific surface area, shape, agglomeration state, and surface functionalization/charge (aminopropyltriethoxysilane). An impact on the cytotoxicity and to a lesser extent on the proinflammatory responses depending on cell type was observed, namely, smaller, large-agglomerated TiO2-NPs were shown to be less toxic than P25, whereas rod-shaped TiO2-NPs were found to be more toxic. Besides, the positively charged particle was slightly more toxic than the negatively charged one. Contrarily, TiO2-NPs, whatever their physicochemical properties, did not induce significant ROS production in both cell systems compared to nontreated control groups. These results may contribute to a better understanding of TiO2-NPs toxicity in relation with their physicochemical features.

Structural Anomalies and Electronic Properties of an Ionic Liquid under Nanoscale Confinement.

Ionic liquids (ILs) promise far greater electrochemical performance compared to aqueous systems, yet key physicochemical properties governing their assembly at interfaces within commonly used graphitic nanopores remain poorly understood. In this work, we combine synchrotron X-ray scattering with first-principles molecular dynamics simulations to unravel key structural characteristics of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([TFSI]-) ionic liquids confined in carbon slit pores. X-ray scattering reveals selective pore filling due to size exclusion, while filled pores exhibit disruption in the IL intermolecular structure, the extent of which increases for narrower slit pores. First-principles simulations corroborate this finding and quantitatively describe how perturbations in the local IL structure, particularly the hydrogen-bond network, depend strongly on the degree of confinement. Despite significant deviations in structure under confinement, electrochemical stability remains intact, which is important for energy storage based on nanoporous carbon electrodes (e.g., supercapacitors).

A Bis-organosilyl-Functionalized Wells-Dawson Polyoxometalate as a Platform for Facile Amine Postfunctionalization.

The development of modular platforms that can undergo postfunctionalization reactions permits coupling of inorganic clusters with different organic functionalities, thereby expanding the range of key physicochemical properties that are relevant for applications in different areas of science. In this work, a novel hybrid Wells-Dawson polyoxometalate (POM) platform was developed and successfully used for postfunctionalization via a nucleophilic substitution reaction. Two new halogen-functionalized bis-organosilyl Wells-Dawson POMs TBA6[α2-P2W17O61{O(SiC3H6-X)2}] (X = Cl or I) were synthesized, and their coupling with amine substrates was explored in a one-step postfunctionalization reaction. The iodide form of the POM has proven to be much more reactive, and its reaction with a range of primary and secondary amines resulted in a series of new bis-substituted Wells-Dawson POMs with the general formula TBA6[α2-P2W17O61{O(SiC3H6-NR1R2)2}]. Coupling of 18 amines with R1 and R2 groups, which exhibited a wide variety in terms of both chemical nature and bulkiness, was achieved under mild conditions via a catalyst-free approach. Using Na2CO3 as a base in acetonitrile solutions at 55 °C resulted in hybrid products that were obtained in high purity and good yields, after a simple isolation and purification procedure.

Engineering the drug carrier biointerface to overcome biological barriers to drug delivery.

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery. In this review, we examine how key material design parameters lead to dynamic biointerfaces and improved drug delivery across biological barriers. We provide a brief overview of approaches used to engineer key physicochemical properties of drug carriers, such as morphology, surface chemistry, and topography, as well as the development of dynamic responsive materials for barrier navigation. We then discuss essential biological barriers and how biointerface engineering can enable drug carriers to better navigate and overcome these barriers to drug delivery.

Using soil bacterial communities to predict physico-chemical variables and soil quality

BackgroundSoil ecosystems consist of complex interactions between biological communities and physico-chemical variables, all of which contribute to the overall quality of soils. Despite this, changes in bacterial communities are ignored by most soil monitoring programs, which are crucial to ensure the sustainability of land management practices. We applied 16S rRNA gene sequencing to determine the bacterial community composition of over 3000 soil samples from 606 sites in New Zealand. Sites were classified as indigenous forests, exotic forest plantations, horticulture, or pastoral grasslands; soil physico-chemical variables related to soil quality were also collected. The composition of soil bacterial communities was then used to predict the land use and soil physico-chemical variables of each site.ResultsSoil bacterial community composition was strongly linked to land use, to the extent where it could correctly determine the type of land use with 85% accuracy. Despite the inherent variation introduced by sampling across ~ 1300 km distance gradient, the bacterial communities could also be used to differentiate sites grouped by key physico-chemical properties with up to 83% accuracy. Further, individual soil variables such as soil pH, nutrient concentrations and bulk density could be predicted; the correlations between predicted and true values ranged from weak (R2 value = 0.35) to strong (R2 value = 0.79). These predictions were accurate enough to allow bacterial communities to assign the correct soil quality scores with 50–95% accuracy.ConclusionsThe inclusion of biological information when monitoring soil quality is crucial if we wish to gain a better, more accurate understanding of how land management impacts the soil ecosystem. We have shown that soil bacterial communities can provide biologically relevant insights on the impacts of land use on soil ecosystems. Furthermore, their ability to indicate changes in individual soil parameters shows that analysing bacterial DNA data can be used to screen soil quality.ByKu94ww1-1K9vBDz2Q4_dVideo

Understanding the synergistic effect of physicochemical properties of nanoparticles and their cellular entry pathways

Gaining precise control over the cellular entry pathway of nanomaterials is key in achieving cytosolic delivery, accessing subcellular environments, and regulating toxicity. However, this precise control requires a fundamental understanding of the behavior of nanomaterials at the bio-nano interface. Herein, we report a computational study investigating the synergistic effect of several key physicochemical properties of nanomaterials on their cellular entry pathways. By examining interactions between monolayer-protected nanoparticles and model cell membranes in a three-dimensional parameter space of size, surface charge/pKa, and ligand chemistry, we observed four different types of nanoparticle translocation for cellular entry which are: outer wrapping, free translocation, inner attach, and embedment. Nanoparticle size, surface charge/pKa, and ligand chemistry each play a unique role in determining the outcome of translocation. Specifically, membrane local curvature induced by nanoparticles upon contact is critical for initiating the translocation process. A generalized paradigm is proposed to describe the fundamental mechanisms underlying the bio-nano interface.

Drug Discovery for Multiple Hereditary Exostoses

Multiple hereditary exostoses (MHE) is an autosomal dominant disorder that results from heterozygous loss‐of‐function genetic mutations in exostosin 1 (EXT1) or exostosin 2 (EXT2). One in 50,000 children worldwide are affected by this relatively rare pediatric disease, which is characterized by osteochondromas that form next to the growth plates of skeletal elements. EXT1 and EXT2 encode the copolymerase responsible for biosynthesis of the backbone of heparan sulfate (HS), a cell surface polysaccharide. Heterozygous mutations in EXT1 or EXT2 lead to shortened HS chains in plasma and various tissues. Currently, there are no approved therapies for this disease; therefore, there is much interest in preventing and/or slowing the growth of exostoses through the development of small molecules that enhance HS levels on the cell surface. In this study, a high‐throughput phenotypic screen was developed to discover potential small molecule drug candidates that augment HS expression in mammalian cells. Screening of a compound library of ~57,000 molecules resulted in the discovery of several N‐aryl‐2‐aminothiazoles that displayed favorable “drug‐like” physicochemical properties, exhibited minimal cytotoxicity, and enhanced HS expression up to 3‐fold on the cell surface. Preliminary studies of structure‐activity relationships identified active analogs of the primary hit and key physicochemical properties required for their biological activity. Ongoing studies aim to expand the SAR studies, identification of a preferred candidate for in vivo studies, and finding the biological target for these compounds. Overall, these studies provide a promising new avenue for the development of novel therapies for MHE and other disorders involving glycosaminoglycan deficiencies.Support or Funding InformationR01AR064202‐03 (to J.E.), K12HL141956 (to R.W.)

Emulsions Stabilized with Alumina-Functionalized Mesoporous Silica Particles.

Alumina-functionalized ordered mesoporous silica SBA-15 particles have been proposed to stabilize Pickering emulsions. Functionalization of SBA-15 particles have been performed by depositing alumina using a two-step synthesis (first, silica condensation, followed by alumina precipitation). Three different Al to Si ratios have been prepared. The calcined materials have been characterized by TEM, SEM, XRD, N2 physisorption, and zeta potential, in order to determine key physicochemical properties, and the alumina localization. The emulsifying and stabilizing properties of the calcined particles have been evaluated for water/toluene-based Pickering emulsions.

Frameshifting preserves key physicochemical properties of proteins

Frameshifts in protein coding sequences are widely perceived as resulting in either nonfunctional or even deleterious protein products. Indeed, frameshifts typically lead to markedly altered protein sequences and premature stop codons. By analyzing complete proteomes from all three domains of life, we demonstrate that, in contrast, several key physicochemical properties of protein sequences exhibit significant robustness against +1 and -1 frameshifts. In particular, we show that hydrophobicity profiles of many protein sequences remain largely invariant upon frameshifting. For example, over 2,900 human proteins exhibit a Pearson's correlation coefficient R between the hydrophobicity profiles of the original and the +1-frameshifted variants greater than 0.7, despite an average sequence identity between the two of only 6.5% in this group. We observe a similar effect for protein sequence profiles of affinity for certain nucleobases as well as protein sequence profiles of intrinsic disorder. Finally, analysis of significance and optimality demonstrates that frameshift stability is embedded in the structure of the universal genetic code and may have contributed to shaping it. Our results suggest that frameshifting may be a powerful evolutionary mechanism for creating new proteins with vastly different sequences, yet similar physicochemical properties to the proteins from which they originate.

Sustainability Analysis of Prosopis juliflora (Sw.) DC Based Restoration of Degraded Land in North India

Restoration of marginal and degraded lands is essential for regaining biodiversity and ecosystems services, and thereby attaining UN-Sustainable Development Goals. During the last few decades, many fast growing and hardy trees have been introduced worldwide to restore the marginal and degraded lands for ecosystem stability. Unfortunately, most of these introduced species have become invasive and invaded the nearby productive systems, leading to significant biodiversity loss and land degradation. Therefore, it is imperative to conduct a sustainability analysis of the introduced species for necessary course correction and also for preventing the future utilisation of such species for land restoration. With this backdrop, the present study was conducted to analyse the socio-ecological impacts of a widely used species, i.e., Prosopis juliflora (Sw.) DC based restoration of degraded land of Lucknow, North India. For this, ecological (soil quality and plant biodiversity) and social (livelihood) indicators have been studied over a period of two years (2015–16) through direct field sampling and questionnaire-based surveys. While there was a positive difference (p &lt; 0.01) in the key physico-chemical properties of the P. juliflora-invaded soil than the non-invaded site, the belowground microbial load was significantly lower (19.46 × 106 g−1 of soil) in invaded land as compared to the non-invaded one (31.01 × 106 g−1). Additionally, the invasion of P. juliflora had significantly reduced the biodiversity by displacing the local flora such as Achyranthes aspera L., Amaranthus spinosus L., Cynodon dactylon (L.) Pers, Euphorbia hirta L., etc. The invaded area had only eight plant species having an effective number of species (ENS) of 7.2, whereas the non-invaded area had the presence of 26 plant species with an ENS of 23.8. Although the local people utilised P. juliflora as fuelwood mostly during summer and winter seasons, the invasion resulted in a fodder deficit of 419.97 kg household−1 y−1 leading to resource scarcity in the invaded area in comparison to the non-invaded area. Ecodistribution mapping clearly showed that P. juliflora is already found in most of the tropical and subtropical countries (~103) including in India and has become invasive in many countries. Therefore, we recommend that P. juliflora must be wisely used for the land restoration programs targeted during the United Nations Decade of Ecosystem Restoration (2021–2030) as this species has invasive traits and thereby reduces the ecosystem sustainability of the invaded areas.

Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)-C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

Applications of nano-porous graphene materials – critical review on performance and challenges

A critical review on the potential of nano-porous graphene materials, their key structural and physicochemical properties for applications in the areas of separation and sensing and energy storage.

Plant invasion alters the physico-chemical dynamics of soil system: insights from invasive Leucanthemum vulgare in the Indian Himalaya.

Understanding the impact of plant invasions on the terrestrial ecosystems, particularly below-ground soil system dynamics can be vital for successful management and restoration of invaded landscapes. Here, we report the impacts of a global plant invader, Leucanthemum vulgare Lam. (ox-eye daisy), on the key physico-chemical soil properties across four sites selected along an altitudinal gradient (1600-2550 m) in Kashmir Himalaya, India. At each site, two types of spatially separated but environmentally similar sampling plots: invaded (IN) and uninvaded (UN) were selected for soil sampling. The results revealed that invasion by L. vulgare had a significant impact on key soil properties in the IN plots. The soil pH, water content, organic carbon and total nitrogen were significantly higher in the IN plots as compared with the UN plots. In contrast, the electrical conductivity, phosphorous and micronutrients, viz. iron, copper, manganese and zinc, were significantly lower in the IN plots as compared with the UN plots. These changes in the soil system dynamics associated with L. vulgare invasion were consistent across all the sites. Also, among the sites, soil properties of low-altitude site (1600 m) were different from the rest of the sampling sites. Overall, the results of the present study indicate that L. vulgare, by altering key properties of the soil system, is likely to influence nutrient cycling processes and facilitates positive feedback for itself. Furthermore, the research insights from this study have wide management implications in the effective ecological restoration of the invaded landscapes.

Comparison of the structural dynamic and mitochondrial electron-transfer properties of the proapoptotic human cytochrome c variants, G41S, Y48H and A51V

Mitochondrial cytochrome c is associated with electron transfer in the respiratory chain and in apoptosis. Four cytochrome c variants have been identified in families that suffer from mild autosomal dominant thrombocytopenia, a platelet disorder associated with increased apoptosis. Three out of the four substitutions, G41S, Y48H and A51V are located on the 40–57 Ω-loop. The G41S and Y48H variants perturb key physicochemical and dynamic properties that result in enhanced functional features associated with apoptotic activity. Herein we characterise the ferric A51V variant. We show by chemical denaturation that this variant causes the native state to be destabilized. Through azide binding kinetics, the population of a pentacoordinate heme form, whereby the Met80 axial ligand is dissociated, is estimated to be of equal magnitude to that found in the Y48H variant. This pentacoordinate form gives rise to peroxidase activity, which despite the similar pentacoordinate population of the A51V variant to that of the Y48H variant, the peroxidase activity of the A51V variant is suppressed. Far-UV circular dichroism spectroscopy and pH jump studies, suggest that a combination of structural and dynamic features in addition to the population of the pentacoordinate form regulate peroxidase activity in these disease variants. Additionally, the steady-state ratio of ferric/ferrous cytochrome c when in turnover with cytochrome c oxidase has been investigated for all 40–57 Ω-loop variants. These studies show that the lower pKa of the alkaline transition for the disease causing variants increases the ferric to ferrous heme ratio, indicating a possible influence on respiration in vivo.

Different drying methods effect on quality attributes of restructured rose powder-yam snack chips

Snacks were prepared by mixing rose powder with yam. Drying techniques, i.e., hot air drying, microwave-vacuum drying (MVD) and microwave-assisted pulse-spouted bed freeze-drying (MPSFD), were evaluated for key physicochemical properties and sensory characteristics of the restructured rose powder-yam (RRY) chips. Color, expansion ratio, bulk density, hardness, total phenolics content and retention of anthocyanins, which are important pigments in rose, were determined. Low-field nuclear magnetic resonance, electronic nose and scanning electron microscopy were used to determine the state of water, odor and microstructure of the samples. MVD required the shortest drying time, while MPSFD gave chips with the best instrumentally-evaluated quality, with the lowest total color difference (ΔE) and hardness. The retention of total phenolics and anthocyanin pigments in RRY chips was highest using MPSFD. MPSFD chips also received the highest scores for all sensory attributes and had a favorable microstructure.