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The prevalence of attention deficit hyperactivity disorder (ADHD), a developmental neuropsychiatric disorder, is high among children and adolescents. The pathogenesis of ADHD is mediated with genetic, biological, and environmental factors. Most therapeutic drugs for ADHD have so far targeted biological causes, primarily by regulating catecholaminergic neurotransmitters. However, ADHD drugs that are clinically treated have various problems in their addictiveness and drug stability; thus, it is recommended that efficacy and safety should be secured through simultaneous prescription of multiple drugs rather than a single drug treatment. Accordingly, it is necessary to develop drugs that newly target pathogenic mechanisms of ADHD. In this study, we attempt to confirm the possibility of developing new drugs by reviewing dopamine-related developmental mechanisms of neurons and their correlation with ADHD. Histone deacetylase inhibitors (HDACi) can regulate the concentration of intracellular dopamine in neurons by expressing vesicular monoamine transporter 2 and inducing the exocytosis of neurotransmitters to the synaptic cleft, thereby promoting the development of neurons and signal transmission. This cellular modulation of HDACi is expected to treat ADHD by regulating endogenous catecholamines such as dopamine. Although studies are still in the preclinical stage, HDAC inhibitors clearly have potential as a therapeutic agent with low addictiveness and high efficacy for ADHD treatment.

Herein, we review the recent progress in the synthesis of representative nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered over 50 years ago, novel practical and asymmetric approaches are still being developed for their synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen and naproxen over the last 10 years is summarized, including developing methodologies, finding novel synthetic routes, and applying continuous-flow chemistry.

Compared with silicon and silicon carbide, diamond has superior material parameters and is therefore suitable for power switching devices. Numerical simulation is important for predicting the electric characteristics of diamond devices before fabrication. Here, we present numerical simulations of p-type diamond pseudo-vertical Schottky barrier diodes using various mobility models. The constant mobility model, based on the parameter μconst, fixed the hole mobility absolutely. The analytic mobility model resulted in temperature- and doping concentration-dependent mobility. An improved model, the Lombard concentration, voltage, and temperature (CVT) mobility model, considered electric field-dependent mobility in addition to temperature and doping concentration. The forward voltage drop at 100 A/cm2 using the analytic and Lombard CVT mobility models was 2.86 and 5.17 V at 300 K, respectively. Finally, we used an empirical mobility model based on experimental results from the literature. We also compared the forward voltage drop and breakdown voltage of the devices, according to variations in p- drift layer thickness and cathode length. The device successfully achieved a low specific on-resistance of 6.8 mΩ∙cm2, a high breakdown voltage of 1190 V, and a high figure-of-merit of 210 MW/cm2.

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (DG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK. [ABSTRACT FROM AUTHOR]

Virtual reality (VR) is an advanced technology widely used in many fields. Education is essential for human resources development, and the use of technology in education can enhance teaching and learning methods. This study aims to present new methods and tools for visual and interactive education in organic chemistry. The experimental design and chemical equipment used in this research are based on the basic theory of organic chemistry, and the related materials are simulated as three-dimensional (3D) models to perform the experiments in a VR system. Chemical reactions are simulated by mixing the chemicals, and the students can observe the chemical reactions that occur. In addition, we measured the impact of using virtual organic chemistry experiments. The system was evaluated by students of the organic chemistry department, and the effectiveness of the experimental apparatus was evaluated in discussions and surveys. The results indicate that VR technologies may be considered suitable for adoption as an accessible educational tool, and that simulating laboratory circumstances through a VR system can improve students’ learning outcomes in experimental chemistry. [ABSTRACT FROM AUTHOR]

A Dielectric Elastomer Actuator (DEA) consists of electrodes with a dielectric layer between them. By controlling the design of the electrodes, voltage, and frequency, the operating range and speed of the DEA can be adjusted. These DEAs find applications in biomimetic robots, artificial muscles, and similar fields. When voltage is applied to the DEA, the dielectric layer undergoes compression and expansion due to electrostatic forces, which can lead to electrical breakdown. This phenomenon is closely related to the performance and lifespan of the DEA. To enhance stability and improve dielectric properties, a DEA Reservoir layer is introduced. Here, stability refers to the ability of the DEA to perform its functions even as the applied voltage increases. The Reservoir layer delays electrical breakdown and enhances stability due to its enhanced thickness. The proposed DEA in this paper is composed of a Reservoir layer and electrode layer. The Reservoir layer is placed between the electrode layers and is independently configured, not subjected to applied voltage like the electrode layers. The performance of the DEA was evaluated by varying the number of polymer layers in the Reservoir and electrode designs. Introducing the Reservoir layer improved the dielectric properties of the DEA and delayed electrical breakdown. Increasing the dielectric constant through the DEA Reservoir can enhance output characteristics in response to electrical signals. This approach can be utilized in various applications in wearable devices, artificial muscles, and other fields.

Every year, almost 4 million patients received medical care for knee osteoarthritis. Osteoarthritis involves progressive deterioration or degenerative changes in the cartilage, leading to inflammation and pain as the bones and ligaments are affected. To enhance treatment and surgical outcomes, various studies analyzing the biomechanics of the human skeletal system by fabricating simulated bones, particularly those reflecting the characteristics of patients with knee osteoarthritis, are underway. In this study, we fabricated replicated bones that mirror the bone characteristics of patients with knee osteoarthritis and developed a skeletal model that mimics the actual movement of the knee. To create patient-specific replicated bones, models were extracted from computerized tomography (CT) scans of knee osteoarthritis patients. Utilizing 3D printing technology, we replicated the femur and tibia, which bear the weight of the body and support movement, and manufactured cartilage capable of absorbing and dispersing the impact of knee joint loads using flexible polymers. Furthermore, to implement knee movement in the skeletal model, we developed artificial muscles based on shape memory alloys (SMAs) and used them to mimic the rolling, sliding, and spinning motions of knee flexion. The knee movement was investigated by changing the SMA spring’s position, the number of coils, and the applied voltage. Additionally, we developed a knee-joint-mimicking system to analyze the movement of the femur. The proposed artificial-skeletal-model-based knee-joint-mimicking system appears to be applicable for analyzing skeletal models of knee patients and developing surgical simulation equipment for artificial joint replacement surgery.

Knee osteoarthritis (OA), also known as degenerative arthritis, is a disease characterized by irreversible changes in the cartilage and bones comprising the joints, resulting in pain, impaired function, and deformity. Furthermore, independent of natural aging, the rate of change in joint cartilage has increased in recent years, which is mainly attributed to environmental factors. The rising incidence of knee-related disorders emphasizes the importance of analyzing the morphology and kinematics of knee structure. This study introduces a knee measurement system designed to replicate the motions of knee using 3D-printing technology, providing insights into knee mechanics with OA level. The research explores the stages of OA using the Kellgren–Lawrence (KL) grade scale, highlighting the variations in the force applied to the knee bone according to movement. The developed knee-simulation system, utilizing the four-bar-link theory, presents a novel approach to studying OA levels 0 to 4. As OA progresses, the cartilage deteriorates, affecting the movement of OA. The OA-based knee measurement system that incorporates soft tissues and skeletons can assist in developing a personalized diagnostic approach for knee disease. This will also help to enhance surgical effectiveness by facilitating the creation of personalized prosthetic joints for individual patients and offering a customized surgical simulation.

Textiles composed of fibers can have their mechanical properties adjusted by changing the arrangement of the fibers, such as strength and flexibility. Particularly, in the case of smart textiles incorporating active materials, various deformations could be created based on fiber patterns that determine the directivity of active materials. In this study, we design a smart fiber-based textile actuator with a chain structure and evaluate its actuation characteristics. Smart fiber composed of shape memory alloy (SMA) generates deformation when the electric current is applied, causing the phase transformation of SMA. We fabricated the smart chain column and evaluated its actuating mechanism based on the size of the chain and the number of rows. In addition, a crochet textile actuator was designed using interlooping smart chains and developed into a soft gripper that can grab objects. With experimental verifications, this study provides an investigation of the relationship between the chain actuator’s deformation, actuating force, actuator temperature, and strain. The results of this study are expected to be relevant to textile applications, wearable devices, and other technical fields that require coordination with the human body. Additionally, it is expected that it can be utilized to configure a system capable of flexible operation by combining rigid elements such as batteries and sensors with textiles.

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 °C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding α-acylthio-α-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee). [ABSTRACT FROM AUTHOR]

Soft actuators that execute diverse motions have recently been proposed to improve the usability of soft robots. Nature-inspired actuators, in particular, are emerging as a means of accomplishing efficient motions based on the flexibility of natural creatures. In this research, we present an actuator capable of executing multi-degree-of-freedom motions that mimics the movement of an elephant’s trunk. Shape memory alloys (SMAs) that actively react to external stimuli were integrated into actuators constructed of soft polymers to imitate the flexible body and muscles of an elephant’s trunk. The amount of electrical current provided to each SMA was adjusted for each channel to achieve the curving motion of the elephant’s trunk, and the deformation characteristics were observed by varying the quantity of current supplied to each SMA. It was feasible to stably lift and lower a cup filled with water by using the operation of wrapping and lifting objects, as well as effectively performing the lifting task of surrounding household items of varying weights and forms. The designed actuator is a soft gripper that incorporates a flexible polymer and an SMA to imitate the flexible and efficient gripping action of an elephant trunk, and its fundamental technology is expected to be used as a safety-enhancing gripper that requires environmental adaptation.

As the use of drones grows, so too does the demand for physical protection against drone damage resulting from collisions and falls. In addition, as the flight environment becomes more complicated, a shock absorption system is required, in which the protective structure can be deformed based on the circumstances. Here, we present an origami- and kirigami-based structure that provides protection from various directions. This research adds a deformation capacity to existing fixed-shape guards; by using shape memory alloys, the diameter and height of the protective structure are controlled. We present three protective modes (1: large diameter/low height; 2: small diameter/large height; and 3: lotus shaped) that mitigate drone falls and side collisions. From the result of the drop impact test, mode 2 showed a 78.2% reduction in the maximum impact force at side impact. We incorporated kirigami patterns into the origami structures in order to investigate the aerodynamic effects of the hollow patterns. Airflow experiments yielded a macro understanding of flow-through behaviors on each kirigami pattern. In the wind speed experiment, the change in airflow velocity induced by the penetration of the kirigami pattern was measured, and in the force measurement experiment, the air force applied to the structure was determined.

In recent years, many researchers have aimed to construct robotic soft grippers that can handle fragile or unusually shaped objects without causing damage. This study proposes a smart textile-composite actuator and its application to a soft robotic gripper. An active fiber and an inactive fiber are combined together using knitting techniques to manufacture a textile actuator. The active fiber is a shape memory alloy (SMA) that is wire-wrapped with conventional fibers, and the inactive fiber is a knitting yarn. A knitted textile structure is flexible, with an excellent structure retention ability and high compliance, which is suitable for developing soft grippers. A driving source of the actuator is the SMA wire, which deforms under heating due to the shape memory effect. Through experiments, the course-to-wale ratio, the number of bundling SMA wires, and the driving current value needed to achieve the maximum deformation of the actuator were investigated. Three actuators were stitched together to make up each finger of the gripper, and layer placement research was completed to find the fingers’ suitable bending angle for object grasping. Finally, the gripping performance was evaluated through a test of grasping various object shapes, which demonstrated that the gripper could successfully lift flat/spherical/uniquely shaped objects.

Several composite materials are being investigated as reinforcement fillers for surgery simulations. This study presents an artificial composite material with properties similar to those of the human bone, which may be used in surgery simulations. Moreover, considering the potential toxicity of debris generated during sawing, a safe epoxy-based composite material was synthesized using cellulose nanocrystals (CNCs) and bioceramics (i.e., hydroxyapatite, Yttria stabilized zirconia oxide, Zirconia oxide), which were used to mimic the stiffness of human bone. To examine the change in mechanical properties according to the composition, 1, 3, and 5 wt% of CNCs were mixed with 5 wt% of the bioceramics. When CNCs were added at 1 wt%, there was a confirmed change in the non-linear stiffness and ductility. The CNC-added specimen fractured when forming a nano-network around the local CNCs during curing. In contrast, the specimen without CNCs was more densely structured, and combined to form a network of all specimens such that a plastic region could exist. Thus, this study successfully manufactured a material that could mimic longitudinal and transverse characteristics similar to those of real human bone, as well as exhibit mechanical properties such as strength and stiffness. Bioceramics are harmless to the human body, and can be used by controlling the added quantity of CNCs. We expect that this material will be suitable for use in surgery simulations.

An efficient enantioselective synthetic method for α-amido-α-alkylmalonates via phase-transfer catalytic α-alkylation was successfully developed. The α-alkylation of α-amidomalonates under phase-transfer catalytic conditions (50% KOH, toluene, -40 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded the corresponding α-amido-α-alkylmalonates in high chemical yields (up to 99%) and optical yields (up to 97% ee), which could be readily converted to versatile chiral intermediates bearing α-amino quaternary stereogenic centers. The synthetic potential of this methodology was demonstrated via the synthesis of chiral azlactone, oxazoline, and unnatural α-amino acid. [ABSTRACT FROM AUTHOR]

In this study, we have deposited organic-inorganic hybrid semiconducting hydroquinone (HQ)/zinc oxide (ZnO) superlattices using molecular-atomic layer deposition, which enables accurate control of film thickness, excellent uniformity, and sharp interfaces at a low deposition temperature (150 °C). Self-limiting growth of organic layers is observed for the HQ precursor on ZnO surface. Nano-laminates were prepared by varying the number of HQ to ZnO cycles in order to investigate the physical and electrical effects of different HQ to ZnO ratios. It is indicated that the addition of HQ layer results in enhanced mobility and reduced carrier concentration. The highest Hall mobility of approximately 2.3cm²/V s and the lowest n-type carrier concentration of approximately 1.0 x 1018/cm³ were achieved with the organic-inorganic superlattice deposited with a ratio of 10 ZnO cycles to 1 HQ cycle. This study offers an approach to tune the electrical transport characteristics of ALD ZnO matrix thin films using an organic dopant. Moreover, with organic embedment, this nano-laminate material may be useful for flexible electronics. [ABSTRACT FROM AUTHOR]

Cachexia, which is characterised by the wasting of fat and skeletal muscles, is the most common risk factor for increased mortality rates among patients with advanced lung cancer. PTHLH (parathyroid hormone-like hormone) is reported to be involved in the pathogenesis of cancer cachexia. However, the molecular mechanisms underlying the regulation of PTHLH expression and the inhibitors of PTHLH have not yet been identified. The PTHLH mRNA levels were measured using quantitative real-time polymerase chain reaction, while the PTHrP (parathyroid hormone-related protein) expression levels were measured using Western blotting and enzyme-linked immunosorbent assay. The interaction between TCF4 (Transcription Factor 4) and TWIST1 and the binding of the TCF4–TWIST1 complex to the PTHLH promoter were analysed using co-immunoprecipitation and chromatin immunoprecipitation. The results of the mammalian two-hybrid luciferase assay revealed that emodin inhibited TCF4–TWIST1 interaction. The effects of Polygonum cuspidatum extract (Pc-Ex), which contains emodin, on cachexia were investigated in vivo using A549 tumour-bearing mice. Ectopic expression of TCF4 upregulated PTHLH expression. Conversely, TCF4 knockdown downregulated PTHLH expression in lung cancer cells. The expression of PTHLH was upregulated in cells ectopically co-expressing TCF4 and TWIST1 when compared with that in cells expressing TCF4 or TWIST1 alone. Emodin inhibited the interaction between TCF4 and TWIST1 and consequently suppressed the TCF4/TWIST1 complex-induced upregulated mRNA and protein levels of PTHLH and PTHrP. Meanwhile, emodin-containing Pc-Ex significantly alleviated skeletal muscle atrophy and downregulated fat browning-related genes in A549 tumour-bearing mice. Emodin-containing Pc-Ex exerted therapeutic effects on lung cancer-associated cachexia by inhibiting TCF4/TWIST1 complex-induced PTHrP expression.

RF-sputtered Ga2O3 passivation was used to fabricate AlGaN/GaN high-electron-mobility transistors (HEMTs) with high breakdown voltage (VBR). The authors varied RF-sputtering power from 50 to 200 W to optimize the HEMTs' blocking characteristics, such as VBR and leakage current. When a gate-source voltage (VGS) of -10 V and drain-source voltage (VDS) of 100 V were applied, 10-nm-thick Ga2O3-passivated HEMTs exhibited drain leakage currents of 63nA/mm, 237 nA/mm, 1.7 µA/mm, and 181 µA/mm when sputtered at 50, 100, 150, and 200 W, respectively, compared with 52 µA/mm for an unpassivated HEMT. Ga2O3-passivated HEMTs with gate-drain distances (LGD) of 20 µm sputtered at 50, 100, 150, and 200 W exhibited VBR values of 1430, 890, 820, and 460 V, respectively, compared to 520 V for the unpassivated HEMT. VBR was decreased when the Ga2O3 passivation layer was deposited at a high sputtering power because of considerable sputtering damage to the AlGaN/GaN heterostructure. Also, VBR of the HEMTs that were Ga2O3-passivated at a low sputtering power increased linearly with LGD because electrons injected into the unintentionally formed vacancies in the Ga2O3 passivation layer effectively extended the depletion region between the gate and drain. The authors achieved a high VBR exceeding 2700 V at a sputtering power of 50 W and LGD of 40 µm. [ABSTRACT FROM AUTHOR]

A new junction termination method employing shallow trenches filled with oxide, which successfully decreased the junction termination area, is proposed and fabricated without any complicated process such as Si-deep etching. Shallow trenches between the floating field limiting rings successfully redistributed the single electric field peak into two peaks so that the breakdown voltage could be increased with the same junction termination area. The experimental results show that the proposed method decreased the junction termination area by more than 25% compared to a conventional field limiting ring structure when breakdown voltages are equal. Index Terms—Breakdown voltage; junction termination; trench. [ABSTRACT FROM AUTHOR]

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population.

P-type diamond devices have high potential for power semiconductors due to their high critical field, hole mobility, and thermal conductivity. The electrical characteristics of p-type pseudovertical diamond Schottky barrier diodes (SBDs) were investigated by numerical simulation. The impact ionization coefficients were required to obtain the breakdown voltage. They were revised to satisfy a parallel-plane breakdown field of 10 MV/cm. The doping concentration and thickness of a low-doped drift layer were key parameters in determining the parallel-plane breakdown voltage. The p-type pseudovertical diamond SBDs exhibited lower breakdown voltage than the parallel-plane breakdown voltage because field crowding occurred at the edge of the cathode. When the doping concentration and thickness of the p− drift layer were 1016 cm−3 and 4 µm, respectively, the breakdown voltage of the p-type pseudovertical diamond SBD was 961 V, which was considerably less than the parallel-plane breakdown voltage of 3646 V. [ABSTRACT FROM AUTHOR]

We demonstrate the fabrication of 7-octenytrichlorosilane (7-OTS)/trimethylaluminum (TMA) organic–inorganic hybrid films using molecular-atomic layer deposition (MALD). The properties of 7-OTS/TMA hybrid films are extensively investigated using transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and electrical measurements. Our results suggest that uniform and smooth amorphous hybrid thin films with excellent insulating properties are obtained using the MALD process. Films have a relatively high dielectric constant of approximately 5.0 and low leakage current density. We fabricate zinc oxide (ZnO) based thin film transistors (TFTs) using 7-OTS/TMA hybrid material as a back gate dielectric with the top ZnO channel layer deposited in-situ via MALD. The ZnO TFTs exhibit a field effect mobility of approximately 0.43 cm2 V−1 s−1, a threshold voltage of approximately 1 V, and an on/off ratio of approximately 103 under low voltage operation (from −3 to 9 V). This work demonstrates an organic–inorganic hybrid gate dielectric material potentially useful in flexible electronics application. [ABSTRACT FROM AUTHOR]

Device fabrication using nanostructured materials, such as nanotubes, requires appropriate metal interconnections between nanotubes and electrical probing pads. Here, electron-beam-assisted deposition (EBAD) and ion-beam-assisted deposition (IBAD) techniques for fabrication of Pt interconnections for single TiO2 nanotube devices are investigated. IBAD conditions were optimized to reduce the leakage current as a result of Pt spreading. The resistivity of the IBAD-Pt was about three orders of magnitude less than that of the EBAD-Pt, due to low carbon concentration and Ga doping, as indicated by X-ray photoelectron spectroscopy analysis. The total resistances of single TiO2 nanotube devices with EBAD- or IBAD-Pt interconnections were 3.82 × 1010 and 4.76 × 108 Ω, respectively. When the resistivity of a single nanotube is low, the high series resistance of EBAD-Pt cannot be ignored. IBAD is a suitable method for nanotechnology applications, such as photocatalysis and biosensors. [ABSTRACT FROM AUTHOR]

Abstract Coronavirus disease 2019 (COVID-19) is a recent pandemic that caused serious global emergency. To identify new and effective therapeutics, we employed a drug repurposing approach. The poly (ADP ribose) polymerase inhibitors were used for this purpose and were repurposed against the main protease (Mpro) target of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). The results from these studies were used to design compounds using the ‘Grow Scaffold’ modules available on Discovery Studio v2018. The three designed compounds, olaparib 1826 and olaparib 1885, and rucaparib 184 demonstrated better CDOCKER docking scores for Mpro than their parent compounds. Moreover, the compounds adhered to Lipinski’s rule of five and demonstrated a synthetic accessibility score of 3.55, 3.63, and 4.30 for olaparib 1826, olaparib 1885, and rucaparib 184, respectively. The short-range Coulombic and Lennard-Jones potentials also support the potential binding of the modified compounds to Mpro. Therefore, we propose these three compounds as novel SARS-CoV-2 inhibitors.

Tuberculosis (TB) in one of the dreadful diseases present globally. This is caused by Mycobacterium tuberculosis. Mycobacterium tuberculosis dethiobiotin synthetase (MtDTBS) is an essential enzyme in biotin biosynthesis and is an ideal target to design and develop novel inhibitors. In order to effectively combat this disease six natural compound (butein) analogues were subjected to molecular docking to determine their binding mode and the binding affinities. The resultant complex structures were subjected to 500 ns simulation run to estimate their binding stabilities using GROMACS. The molecular dynamics simulation studies provided essential evidence that the systems were stable during the progression of 500 ns simulation run. The root mean square deviation (RMSD) of all the systems was found to be below 0.3 nm stating that the systems are well converged. The radius of gyration (Rg) profiles indicated that the systems were highly compact without any major fluctuations. The principle component analysis (PCA) and Gibbs energy landscape studies have revealed that the comp3, comp5 and comp11 systems navigated marginally through the PC2. The intermolecular interactions have further demonstrated that all the compounds have displayed key residue interactions, firmly holding the ligands at the binding pocket. The residue Lys37 was found consistently to interact with all the ligands highlighting its potential role in inhibiting the MtDTBS. Our investigation further put forth two novel compounds (comp10 and comp11) as putative antituberculosis agents. Collectively, we propose six compounds has plausible inhibitors to curtail TB and further can act as scaffolds in designing new compounds.

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.

Cysteine–cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC50 value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.

A 7-step enantioselective synthetic method for preparing (S)(+)-coerulescine is reported through the use of diphenylmethyl tert-butyl α-(2-nitrophenyl)malonate (16% overall yield, >99% ee). Allylation is the key step under phase-transfer catalytic conditions (86% ee). This synthetic method can be used as a practical route for the synthesis of various derivatives of (S)(+)-coerulescine for analyzing its structure–activity relationships against its biological activities.

Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections and small-molecule libraries for high-throughput screening (HTS) and high-content screening (HCS) has emerged as a powerful tool in the development of novel therapeutic agents. Herein, we review the recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries.

Diarrheal diseases due to foodborne Escherichia coli are the leading cause of illness in humans. Here, we performed pathogenic typing, molecular typing, and antimicrobial susceptibility tests on seventy-five isolates of E. coli isolated from stool samples of patients suffering from foodborne diseases in Busan, South Korea. All the isolates were identified as E. coli by both biochemical analysis (API 20E system) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). The bacteria displayed entero-pathogenic E. coli (EPEC) (47.0%), entero-aggregative E. coli (EAEC) (33.3%), entero-toxigenic E. coli (ETEC) (6.6%), ETEC and EPEC (6.6%), EPEC and EAEC (4%), and ETEC and EAEC (2.7%) characteristics. The E. coli isolates were highly resistant to nalidixic acid (44.0%), tetracycline (41.3%), ampicillin (40%), ticarcillin (38.7%), and trimethoprim/sulfamethoxazole (34.7%); however, they were highly susceptible to imipenem (98.6%), cefotetan (98.6%), cefepime (94.6%), and chloramphenicol (94.6%). Although 52 strains (69.3%) showed resistance against at least 1 of the 16 antibiotics tested, 23 strains (30.7%) were susceptible to all the antibiotics. Nine different serotypes (O166, O8, O20, O25, O119, O159, O28ac, O127a, and O18), five genotypes (I to V, random-amplified polymorphic DNA), and four phenotypes (A to D, MALDI-TOF MS) were identified, showing the high level of heterogeneity between the E. coli isolates recovered from diarrheal patients in South Korea.

Widely used in global households, fenugreek is well known for its culinary and medicinal uses. The various reported medicinal properties of fenugreek are by virtue of the different natural phytochemicals present in it. Regarded as a promising target, interleukin 2 receptor subunit alpha (IL2Rα) has been shown to influence immune responses. In the present research, using in silico techniques, we have demonstrated the potential IL2Rα binding properties of three polyphenol stilbenes (desoxyrhaponticin, rhaponticin, rhapontigenin) from fenugreek. As the first step, molecular docking was performed to assess the binding potential of the fenugreek phytochemicals with IL2Rα. All three phytochemicals demonstrated interactions with active site residues. To confirm the reliability of our molecular docking results, 100 ns molecular dynamics simulations studies were undertaken. As discerned by the RMSD and RMSF analyses, IL2Rα in complex with the desoxyrhaponticin, rhaponticin, and rhapontigenin indicated stability. The RMSD analysis of the phytochemicals alone also demonstrated no significant structural changes. Based on the stable molecular interactions and comparatively slightly better MM/PBSA binding free energy, rhaponticin seems promising. Additionally, ADMET analysis performed for the stilbenes indicated that all of them obey the ADMET rules. Our computational study thus supports further in vitro IL2Rα binding studies on these stilbenes, especially rhaponticin.

A great effort to discover new therapeutic ingredients is often initiated through the discovery of the existence of novel marine natural products. Since substances produced by the marine environment might be structurally more complex and unique than terrestrial natural products, there have been cases of misassignments of their structures despite the availability of modern spectroscopic and computational chemistry techniques. When it comes to refutation to erroneously or tentatively proposed structures empirical preparations through organic chemical synthesis has the greatest contribution along with close and sophiscated inspection of spectroscopic data. Herein, we analyzed the total synthetic studies that have decisively achieved in revelation of errors, ambiguities, or incompleteness of the isolated structures of marine natural products covering the period from 2018 to 2021.

Organic light-emitting diodes with thermally activated delayed fluorescence emitter have been developed with highly twisted donor–acceptor configurations and color-pure blue emitters. Synthesized 4-(4-(4,6-diphenylpyrimidin-2-yl)phenyl)-10H-spiro[acridine-9,9′-fluorene] (4,6-PhPMAF) doped device with spiroacridine as a donor unit and diphenylpyrimidine as acceptor exhibits the device characteristics such as the luminescence, external quantum efficiencies, current efficiencies, and power efficiencies corresponding to 213 cd/m2, 2.95%, 3.27 cd/A, and 2.94 lm/W with Commission International de l'Eclairage (CIE) coordinates of (0.15, 0.11) in 4,6-PhPMAF-doped DPEPO emitter. The reported 10-(4-(2,6-diphenylpyrimidin-4-yl)phenyl)-10H-spiro[acridine-9,9′-fluorene] (2,6-PhPMAF) doped device exhibit high device performance with 1,445 cd/m2, 12.38%, 19.6 cd/A, and 15.4 lm/W, which might be originated from increased internal quantum efficiency by up-converted triplet excitons to the singlet state with relatively smaller ΔEST of 0.17 eV and higher reverse intersystem crossing rate (kRISC) of 1.0 ×108/s in 2,6-PhPMAF than 0.27 eV and 3.9 ×107/s in 4,6-PhPMAF. Despite low performance of 4,6-PhPMAF doped device, synthesized 4,6-PhPMAF has better color purity as a deep-blue emission with y axis (0.11) than reported 2,6-PhPMAF with y axis (0.19) in CIE coordinate. The synthesized 4,6-PhPMAF has higher thermal stability of any transition up to 300°C and decomposition temperature with only 5% weight loss in 400°C than reported 2,6-PhPMAF. The maximum photoluminescence emission of 4,6-PhPMAF in various solvents appeared at 438 nm, which has blue shift about 20 nm than that of 2,6-PhPMAF, which contributes deep-blue emission in synthesized 4,6-PhPMAF.

The variable lymphocyte receptor (VLR) mediates the humoral immune response in jawless vertebrates, including lamprey (Petromyzon marinus) and hagfish (Eptatretus burgeri). Hagfish VLRBs are composed of leucine-rich repeat (LRR) modules, conjugated with a superhydrophobic C-terminal tail, which contributes to low levels of expression in recombinant protein technology. In this study, we screened Ag-specific VLRBs from hagfish immunized with nervous necrosis virus (NNV). The artificially multimerized form of VLRB was constructed using a mammalian expression system. To enhance the level of expression of the Ag-specific VLRB, mutagenesis of the VLRB was achieved in vitro through domain swapping of the LRR C-terminal cap and variable LRR module. The mutant VLRB obtained, with high expression and secretion levels, was able to specifically recognize purified and progeny NNV, and the Ag binding ability of this mutant was increased by at least 250-fold to that of the nonmutant VLRB. Furthermore, preincubation of the Ag-specific VLRB with NNV reduced the infectivity of NNV in E11 cells in vitro, and in vivo experiment. Our results suggest that the newly developed Ag-specific VLRB has the potential to be used as diagnostic and therapeutic reagents for NNV infections in fish. [ABSTRACT FROM AUTHOR]

The widespread and uncontrollable emergence of antibiotic-resistant bacteria, especially methicillin-resistant Staphylococcus aureus, has promoted a wave of efforts to discover a new generation of antibiotics that prevent or treat bacterial infections neither as bactericides nor bacteriostats. Due to its crucial role in virulence and its nonessentiality in bacterial survival, sortase A has been considered as a great target for new antibiotics. Sortase A inhibitors have emerged as promising alternative antivirulence agents against bacteria. Herein, the structural and preparative aspects of some small synthetic organic compounds that block the pathogenic action of sortase A have been described.