Rational Drug Discovery for Isoxazole Based VEGFR2 Inhibition.

BACKGROUND: Inhibiting receptor-tyrosine-kinase (RTK) signalling pathways has emerged as a key focus of novel cancer therapy development. Vascular endothelial growth factor receptor (VEGFR) is a member of the RTK family and is required for vasculogenesis and angiogenesis. Because VEGFR 2 is the subtype responsible for cellular angiogenesis and vasculogenesis, blocking it will impair tumour cell blood supply, reducing their development, proliferation, and metastasis. AIM & OBJECTIVE: The aim of this study is to obtain an optimised pharmacophore as a VEGFR2 inhibitor using QSAR investigations. This aids in determining the link between structure and activity in new chemical entities (NCEs). MATERIALS AND METHODS: The multi-linear regression approach (MLR) method was utilised to generate the QSAR Model using the programme QSARINS v.2.2.4. RESULTS AND DISCUSSION: For 2D QSAR, the best models produced has correlation coefficients of R2= 0.9396. The 3D-QSAR model obtained with R2= 0.9121 and Q2 = 0.8377. Taking docking observations, pharmacological behaviour, and toxicity analyses into account, most of the derivatives demonstrated VEGFR2 inhibitory competence. CONCLUSION: According to QSAR studies, more electron-donating groups on the benzene ring linked to the isoxazole were shown to be necessary for activity. In molecular docking studies, most compounds have shown stronger affinity for the crucial amino acids Cys:919, Asp:1046, and Glu:885, which are found in typical drugs. All NCEs passed the Lipinski screening.

Development of 7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives Using QSARINS Tool as BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the joints, leading to pain, swelling, and joint deformity. Effective management of RA involves the use of disease-modifying drugs that can slow down disease progression and alleviate symptoms. Among the potential targets for RA treatment is Bruton's tyrosine kinase (BTK), which plays a crucial role in B-cell signalling and contributes to the pathogenesis of RA. AIMS: QSARINS (QSAR-INSUBRIA) is software used for the development and validation of Quantitative Structure-Activity Relationship (QSAR) analysis. In the present work, this software was explored for pharmacophore optimization of the pyrrolo-pyrimidine nucleus for anti-rheumatoid activity. METHODS: A series of pyrrolo-pyrimidine derivatives were used to build the QSAR models. These models were generated to identify structural features that correlate significantly with the activity. We followed the assessment of statistical parameters to ensure thorough validation of all the QSAR models. The QSAR models demonstrating better statistical performance were selected, and descriptors of these models were analysed. RESULTS: The results showed that the QSAR models were highly statistically robust and exhibited a strong external predictive ability. Their structural features were also deduced. CONCLUSION: This QSAR study provided crucial information about the specific molecular features that can be used for the optimization of the pharmacophores. This research provides valuable insights into the structural features essential for BTK inhibition and paves the way for the design and development of novel anti-rheumatic agents targeting BTK in RA.

In-silico studies of 2-aminothiazole derivatives as anticancer agents by QSAR, molecular docking, MD simulation and MM-GBSA approaches.

Targeting Hec1/Nek2 is considered as crucial target for cancer treatment due to its significant role in cell proliferation. In pursuit of this, a series of twenty-five 2-aminothiazoles derivatives, along with their Hec1/Nek2 inhibitory activities were subjected to QSAR studies utilizing QSARINS software. The significant three descriptor QSAR model was generated, showing noteworthy statistical parameters: a correlation coefficient of cross validation leave one out (Q2LOO) = 0.7965, coefficient of determination (R2) = 0.8436, (R2ext) = 0.6308, cross validation leave many out (Q2LMO) = 0.7656, Concordance Correlation Coefficient (CCCCV = 0.8875), CCCtr = 0.9151, and CCCext = 0.0.7241. The descriptors integral to generated QSAR model include Moreau-Broto autocorrelation, which represents the spatial autocorrelation of a property along the molecular graph's topological structure (ATSC1i), Moran autocorrelation at lag 8, which is weighted by charges (MATS8c) and RPSA representing the total molecular surface area. It was noted that these descriptors significantly influence Hec1/Nek2 inhibitory activity of 2-aminothiazoles derivatives. New lead molecules were designed and predicted for their Hec1/Nek2 inhibitory activity based on the developed three descriptor model. Further, the ADMET and Molecular docking studies were carried out for these designed molecules. The three molecules were selected based on their docking score and further subjected for MD simulation studies. Post-MD MM-GBSA analysis were also performed to predicted the free binding energies of molecules. The study helped us to understand the key interactions between 2-aminothiazoles derivatives and Hec1/Nek2 protein that may be necessary to develop new lead molecules against cancer.Communicated by Ramaswamy H. Sarma.

Effect of growth temperature on self-rectifying BaTiO3/ZnO heterojunction for high-density crossbar arrays and neuromorphic computing.

In the quest for high-density integration and massive scalability, ferroelectric-based devices provide an achievable approach for nonvolatile crossbar array (CBA) architecture and neuromorphic computing. In this report, ferroelectric-semiconductor (Pt/BaTiO3/ZnO/Au) heterojunction-based devices are demonstrated to exhibit nonvolatile and synaptic characteristics. In this study, the ferroelectric (BaTiO3) layer was modulated at various growth temperatures of 350 °C, 450 °C, 550 °C and 650 °C. Growing temperature in the ferroelectric layer has a significant impact on resistive switching. The ferroelectricity of the BaTiO3 thin film enhanced by increasing temperature causes a substantial shift in the interface state density at heterojunction interface, which is crucial for self-rectification. Furthermore, this self-rectifying property advances to reduce the crosstalk problem without any selector device. Enhanced resistive switching and neuromorphic applications have been demonstrated using BaTiO3 heterostructure devices at 550 °C. The dynamic ferroelectric polarization switching in this heterojunction demonstrated linear conductance change in artificial synapses with 91 % recognition accuracy. Ferroelectric polarization reversal with a depletion region at the heterojunction interface is the responsible mechanism for the switching in these devices. Thus, these findings pave the way for designing low power high-density crossbar arrays and neuromorphic application based on ferroelectric-semiconductor heterostructures.

Recent progress in energy, environment, and electronic applications of MXene nanomaterials.

Since the discovery of graphene, two-dimensional (2D) materials have gained widespread attention, owing to their appealing properties for various technological applications. Etched from their parent MAX phases, MXene is a newly emerged 2D material that was first reported in 2011. Since then, a lot of theoretical and experimental work has been done on more than 30 MXene structures for various applications. Given this, in the present review, we have tried to cover the multidisciplinary aspects of MXene including its structures, synthesis methods, and electronic, mechanical, optoelectronic, and magnetic properties. From an application point of view, we explore MXene-based supercapacitors, gas sensors, strain sensors, biosensors, electromagnetic interference shielding, microwave absorption, memristors, and artificial synaptic devices. Also, the impact of MXene-based materials on the characteristics of respective applications is systematically explored. This review provides the current status of MXene nanomaterials for various applications and possible future developments in this field.

Optically Reconfigurable Complementary Logic Gates Enabled by Bipolar Photoresponse in Gallium Selenide Memtransistor.

To avoid the complexity of the circuit for in-memory computing, simultaneous execution of multiple logic gates (OR, AND, NOR, and NAND) and memory behavior are demonstrated in a single device of oxygen plasma-treated gallium selenide (GaSe) memtransistor. Resistive switching behavior with RON /ROFF ratio in the range of 104 to 106 is obtained depending on the channel length (150 to 1600 nm). Oxygen plasma treatment on GaSe film created shallow and deep-level defect states, which exhibit carriers trapping/de-trapping, that lead to negative and positive photoconductance at positive and negative gate voltages, respectively. This distinguishing feature of gate-dependent transition of negative to positive photoconductance encourages the execution of four logic gates in the single memory device, which is elusive in conventional memtransistor. Additionally, it is feasible to reversibly switch between two logic gates by just adjusting the gate voltages, e.g., NAND/NOR and AND/NAND. All logic gates presented high stability. Additionally, memtransistor array (1×8) is fabricated and programmed into binary bits representing ASCII (American Standard Code for Information Interchange) code for the uppercase letter "N". This facile device configuration can provide the functionality of both logic and memory devices for emerging neuromorphic computing.

Flexible Organic-Inorganic Halide Perovskite-Based Diffusive Memristor for Artificial Nociceptors.

With the current evolution in the artificial intelligence technology, more biomimetic functions are essential to execute increasingly complicated tasks and respond to challenging work environments. Therefore, an artificial nociceptor plays a significant role in the advancement of humanoid robots. Organic-inorganic halide perovskites (OHPs) have the potential to mimic the biological neurons due to their inherent ion migration. Herein, a versatile and reliable diffusive memristor built on an OHP is reported as an artificial nociceptor. This OHP diffusive memristor showed threshold switching properties with excellent uniformity, forming-free behavior, a high ION/IOFF ratio (104), and bending endurance over >102 cycles. To emulate the biological nociceptor functionalities, four significant characteristics of the artificial nociceptor, such as threshold, no adaptation, relaxation, and sensitization, are demonstrated. Further, the feasibility of OHP nociceptors in artificial intelligence is being investigated by fabricating a thermoreceptor system. These findings suggest a prospective application of an OHP-based diffusive memristor in the future neuromorphic intelligence platform.

In Search of HIV Entry Inhibitors Using Molecular Docking, ADME, and Toxicity Studies of Some Thiazolidinone-Pyrazine Derivatives Against CXCR4 Co-receptor.

BACKGROUND: Entry inhibitors prevent the binding of human immunodeficiency virus protein to the chemokine receptor CXCR4 and are used along with conventional anti-HIV therapy. They aid in restoring immunity and can prevent the development of HIV-TB co-infection. AIMS: In the present study, various thiazolidinone-pyrazine derivatives earlier studied for NNRT inhibition activity were gauged for their entry inhibitor potential. OBJECTIVE: The objective of the study is to perform molecular docking, ADME, toxicity studies of some thiazolidinone-pyrazine derivatives as entry inhibitors targeting CXCR4 co-receptors. METHODS: In-silico docking studies were performed using AutoDock Vina software and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. RESULTS: Taking into consideration the docking results, pharmacokinetic behaviour and toxicity profile, four molecules (compounds 1, 9, 11, and 16) have shown potential as entry inhibitors. CONCLUSION: These compounds have shown potential as both NNRTI and entry inhibitors and hence can be used in management of immune compromised diseases like TB-HIV coinfection.

Stable and Multilevel Data Storage Resistive Switching of Organic Bulk Heterojunction.

Organic nonvolatile memory devices have a vital role for the next generation of electrical memory units, due to their large scalability and low-cost fabrication techniques. Here, we show bipolar resistive switching based on an Ag/ZnO/P3HT-PCBM/ITO device in which P3HT-PCBM acts as an organic heterojunction with inorganic ZnO protective layer. The prepared memory device has consistent DC endurance (500 cycles), retention properties (104 s), high ON/OFF ratio (105), and environmental stability. The observation of bipolar resistive switching is attributed to creation and rupture of the Ag filament. In addition, our conductive bridge random access memory (CBRAM) device has adequate regulation of the current compliance leads to multilevel resistive switching of a high data density storage.

In silico Studies, Synthesis and Antitubercular Activity of Some Novel Quinoline - Azitidinone Derivatives.

BACKGROUND: Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase. OBJECTIVE: The structural features necessary for a good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1- substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents. METHODS: 2D and 3D QSAR analyses were used to designed compounds having a quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. The binding affinity of designed compounds was gauged by molecular docking studies. RESULTS: Statistically significant QSAR models generated by the SA-MLR method for 2D QSAR exhibited r2 = 0.852, q2 = 0.811, whereas 3D QSAR with SA-kNN showed q2 = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(µg/ml). These compounds showed some crucial interaction with MTB ATPase. CONCLUSION: The present study has shown some promising results which can be further explored for lead generation.

Non Nucleoside Reverse Transcriptase Inhibitors, Molecular Docking Studies and Antitubercular Activity of Thiazolidin-4-one Derivatives.

BACKGROUND: Management of Co-existence of Acquired immunodeficiency syndrome and Tuberculosis has become a global challenge due to the emergence of resistant strains and pill burden. OBJECTIVE: Hence the aim of the present work was to design and evaluate compounds for their dual activity on HIV-1 and Tuberculosis (TB). METHODS: A series of seven, novel Thiazolidin-4-one derivatives were synthesized and evaluated for their anti-HIV and anti-tubercular activity along with Molecular docking studies. All the seven compounds displayed promising activity against the replication of HIV-1 in cell-based assays. The four most active compounds were further evaluated against X4 tropic HIV-1UG070 and R5 tropic HIV-1VB59 primary isolates. The binding affinity of all the designed compounds for HIV-RT and Mycobacterium tuberculosis Enol Reductase (MTB InhA) was gauged by molecular docking studies which revealed crucial thermodynamic interactions governing their binding. RESULTS: The CC50 values for the test compounds were in the range of, 15.08-34.9 µg/ml, while the IC50 values were in the range of 16.1-27.13(UG070; X4) and 12.03-23.64 (VB59; R5) µg/ml. The control drug Nevirapine (NVP) exhibited CC50 value of 77.13 µg/ml and IC50 value of 0.03 µg/ml. Amongst all these compounds, compound number 3 showed significant activity with a TI value of 2.167 and 2.678 against the HIV-1 X4 and the R5 tropic virus respectively. In anti-mycobacterial screening, the compounds proved effective in inhibiting the growth of both log phase and starved MTB cultures. CONCLUSION: Compound 3 has been found to be active against HIV-1 as well as MTB.

QSAR, docking studies of 1,3-thiazinan-3-yl isonicotinamide derivatives for antitubercular activity.

The enzyme - enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan-Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r2=0.958, q2=0.922) while 3D QSAR model was derived using the SA KNN method (q2=0.8498). These studies could guide the topological, electrostatic, steric, hydrophobic substitutions around the nucleus based on which the NCEs were designed. Furthermore, molecular docking was performed to gauze the binding affinity of the designed analogues for enoyl ACP reductase enzyme. Amongst all the designed analogues the binding energies of SKS 01 and SKS 05 were found to be -5.267kcal/mol and -5.237kcal/mol respectively which was comparable with the binding energy of the standard Isoniazid (-6.254kcal/mol).

Synthesis and characterization of a novel mucoadhesive derivative of xyloglucan.

A novel polymer in the form of a thiolated derivative of natural tamarind seed polysaccharide or xyloglucan was synthesized and its chacteristics as a mucoadhesive polymer were studied as a part of the study undertaken herein. The synthetic route followed involves a two-step reaction mechanism of firstly oxidizing xyloglucan and then further conjugating it with l-cysteine to form thiolated xyloglucan or thiomer via imine linkage. The thiomer thus formed was characterized using various analytical techniques as differential scanning calorimetry (DSC), X-ray diffraction analysis (XRD), and nuclear magnetic resonance (NMR). Ellman's method was used to determine the numbers of thiol groups/g of thiolated xyloglucan. Zeta potential measurements were carried out for thiolated xyloglucan. Viscosities of the formulated xyloglucan and thiolated xyloglucan gels were comparatively evaluated along with the evaluation of mucoadhesive properties of the gels using ex vivo bioadhesion study employing freshly excised sheep intestinal mucosa.

QSAR and Molecular Docking Studies of Oxadiazole-Ligated Pyrrole Derivatives as Enoyl-ACP (CoA) Reductase Inhibitors.

A quantitative structure-activity relationship model was developed on a series of compounds containing oxadiazole-ligated pyrrole pharmacophore to identify key structural fragments required for anti-tubercular activity. Two-dimensional (2D) and three-dimensional (3D) QSAR studies were performed using multiple linear regression (MLR) analysis and k-nearest neighbour molecular field analysis (kNN-MFA), respectively. The developed QSAR models were found to be statistically significant with respect to training, cross-validation, and external validation. New chemical entities (NCEs) were designed based on the results of the 2D- and 3D-QSAR. NCEs were subjected to Lipinski's screen to ensure the drug-like pharmacokinetic profile of the designed compounds in order to improve their bioavailability. Also, the binding ability of the NCEs with enoyl-ACP (CoA) reductase was assessed by docking.

Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes.

Follistatins are extracellular inhibitors of the TGF-ß family ligands including activin A, myostatin and bone morphogenetic proteins. Follistatin-like 3 (FSTL3) is a potent inhibitor of activin signalling and antagonises the cardioprotective role of activin A in the heart. FSTL3 expression is elevated in patients with heart failure and is upregulated in cardiomyocytes by hypertrophic stimuli, but its role in cardiac remodelling is largely unknown. Here, we show that the production of FSTL3 by cardiomyocytes contributes to the paracrine activation of cardiac fibroblasts, inducing changes in cell adhesion, promoting proliferation and increasing collagen production. We found that FSTL3 is necessary for this response and for the induction of cardiac fibrosis. However, full activation requires additional factors, and we identify connective tissue growth factor as a FSTL3 binding partner in this process. Together, our data unveil a novel mechanism of paracrine communication between cardiomyocytes and fibroblasts that may provide potential as a therapeutic target in heart remodelling.

Biodegradation of crystal violet by Agrobacterium radiobacter.

Agrobacterium radiobacter MTCC 8161 completely decolorized the Crystal Violet with 8 hr (10 mg/L) at static anoxic conditions. The decreased decolorization capability by A. radiobacter was observed, when the Crystal Violet concentration was increased from 10 to 100 mg/L. Semi-synthetic medium containing 1% yeast extract and 0.1% NH4C1 has shown 100% decolorization of Crystal Violet within 5 hr. A complete degradation of Crystal Violet by A. radiobacter was observed up to 7 cycles of repeated addition (10 mg/L). When the effect of increasing inoculum concentration on decolorization of Crystal Violet (100 mg/L) was studied, maximum decolorization was observed with 15% inoculum concentration. A significant increase in the activities of laccase (184%) and aminopyrine N-demethylase (300%) in cells obtained after decolorization indicated the involvement of these enzymes in decolorization process. The intermediates formed during the degradation of Crystal Violet were analyzed by gas chromatography and mass spectroscopy (GC/MS). It was detected the presence of N,N,N',N"-tetramethylpararosaniline, [N, N-dimethylaminophenyl] [N-methylaminophenyl] benzophenone, N, N-dimethylaminobenzaldehyde, 4-methyl amino phenol and phenol. We proposed the hypothetical metabolic pathway of Crystal Violet biodegradation by A. radiobacter. Phytotoxicity and microbial toxicity study showed that Crystal Violet biodegradation metabolites were less toxic to bacteria (A. radiobacter, P. aurugenosa and A. vinelandii) contributing to soil fertility and for four kinds of plants (Sorghum bicolor Vigna radiata, Lens culinaris and Triticum aestivum) which are most sensitive, fast growing and commonly used in Indian agriculture.

Cardiac myocyte-specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy.

Transforming growth factor-ß family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 3 (Fstl3) is an extracellular regulator of certain TGF-ß family members, including activin A. The aim of this study was to examine the role of Fstl3 in cardiac hypertrophy. Cardiac myocyte-specific Fstl3 knock-out (KO) mice and control mice were subjected to pressure overload induced by transverse aortic constriction (TAC). Cardiac hypertrophy was assessed by echocardiography and histological and biochemical methods. KO mice showed reduced cardiac hypertrophy, pulmonary congestion, concentric LV wall thickness, LV dilatation, and LV systolic dysfunction after TAC compared with control mice. KO mice displayed attenuated increases in cardiomyocyte cell surface area and interstitial fibrosis following pressure overload. Although activin A was similarly up-regulated in KO and control mice after TAC, a significant increase in Smad2 phosphorylation only occurred in KO mice. Knockdown of Fstl3 in cultured cardiomyocytes inhibited PE-induced cardiac hypertrophy. Conversely, adenovirus-mediated Fstl3 overexpression blocked the inhibitory action of activin A on hypertrophy and Smad2 activation. Transduction with Smad7, a negative regulator of Smad2 signaling, blocked the antihypertrophic actions of activin A stimulation or Fstl3 ablation. These findings identify Fstl3 as a stress-induced regulator of hypertrophy that controls myocyte size via regulation of Smad signaling.

Decolorization and biodegradation of Reactive Blue 13 by Proteus mirabilis LAG.

The decolorization and biodegradation of Reactive Blue 13 (RB13), a sulphonated reactive azo dye, was achieved under static anoxic condition with a bacterial strain identified as Proteus mirabilis LAG, which was isolated from a municipal dump site soil near Lagos, Nigeria. This strain decolorized RB13 (100mg/l) within 5h. The formation of aromatic amine prior to mineralization was supported by Fourier transform infrared spectrometry (FTIR), which revealed the disappearance of certain peaks, particularly those of the aromatic C-H bending at 600-800 cm(-1). Gas chromatography-mass spectrophotometry (GCMS) analysis of the dye metabolite showed the presence of sodium-2(2-formyl-2-hydroxyvinyl) benzoate, with a tropylium cation as its base peak, this suggested the breakage of naphthalene rings in RB13. The detection of azoreductase and laccase activities suggested the enzymatic reduction of azo bonds prior to mineralization. In addition, phytotoxicity studies indicated the detoxification of RB13 to non-toxic degradation products by this strain of P. mirabilis LAG.

Effect of HEPES buffer on the uptake and transport of P-glycoprotein substrates and large neutral amino acids.

HEPES has been widely employed as an organic buffer agent in cell culture medium as well as uptake and transport experiments in vitro. However, concentrations of HEPES used in such studies vary from one laboratory to another. In this study, we investigated the effect of HEPES on the uptake and bidirectional transport of P-gp substrates employing both Caco-2 and MDCK-MDR1 cells. ATP-dependent uptake of glutamic acid was also examined. ATP production was further quantified applying ATP Determination Kit. An addition of HEPES to the growth and incubation media significantly altered the uptake and transport of P-gp substrates in both Caco-2 and MDCK-MDR1 cells. Uptake of P-gp substrates substantially diminished as the HEPES concentration was raised to 25 mM. Bidirectional (A-B and B-A) transport studies revealed that permeability ratio of P(appB-A) to P(appA-B) in the presence of 25 mM HEPES was significantly higher than control. The uptake of phenylalanine is an ATP-independent process, whereas the accumulation of glutamic acid is ATP-dependent. While phenylalanine uptake remained unchanged, glutamic acid uptake was elevated with the addition of HEPES. Verapamil is an inhibitor of P-gp mediated uptake; elevation of cyclosporine uptake in the presence of 5 muM verapamil was compromised by the presence of 25 mM HEPES. The results of ATP assay indicated that HEPES stimulated the production of ATP. This study suggests that the addition of HEPES in the medium modulated the energy dependent efflux and uptake processes. The effect of HEPES on P-gp mediated drug efflux and transport may provide some mechanistic insight into possible reasons for inconsistencies in the results reported from various laboratories.