Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line.

Triazole-based acetamides serve as important scaffolds for various pharmacologically active drugs. In the present work, structural hybrids of 1,2,4-triazole and acetamides were furnished by chemically modifying 2-(4-isobutylphenyl) propanoic acid (1). Target compounds 7a-f were produced in considerable yields (70-76%) by coupling the triazole of compound 1 with different electrophiles under different reaction conditions. These triazole-coupled acetamide derivatives were verified by physiochemical and spectroscopic (HRMS, FTIR, 13CNMR, and 1HNMR,) methods. The anti-liver carcinoma effects of all of the derivatives against a HepG2 cell line were investigated. Compound 7f, with two methyl moieties at the ortho-position, exhibited the highest anti-proliferative activity among all of the compounds with an IC50 value of 16.782 µg/mL. 7f, the most effective anti-cancer molecule, also had a very low toxicity of 1.190.02%. Molecular docking demonstrates that all of the compounds, especially 7f, have exhibited excellent binding affinities of -176.749 kcal/mol and -170.066 kcal/mol to c-kit tyrosine kinase and protein kinase B, respectively. Compound 7f is recognized as the most suitable drug pharmacophore for the treatment of hepatocellular carcinoma.

Single Organic Ligands Act as a Bifunctional Sensor for Subsequent Detection of Metal and Cyanide Ions, a Statistical Approach toward Coordination and Sensitivity.

The detection of key ions in environmental samples has garnered significant attention in recent years in the pursuit of a cleaner environment for living organisms. Bifunctional and multifunctional sensors, as opposed to single-species sensors, have emerged as a rapidly developing field. Many reports in the literature have documented the use of bifunctional sensors for the subsequent detection of metal and cyanide ions. These sensors, consisting of simple organic ligands, form coordination compounds with transition metal ions, resulting in clear visible or fluorescent changes that facilitate detection. In some cases, a single polymeric material can act as a ligand and coordinate with metal ions, forming a complex that serves as a sensor for cyanide ion detection in biological and environmental samples through various mechanisms. Nitrogen is the most dominant coordinating site in these bifunctional sensors, with the sensitivity of the sensors being directly proportional to the denticities of ligands for metal ions, while for cyanide ions the sensitivity was found independent of the denticity of the ligands. This review covers the progress made in the field over the past fifteen years (2007-2022), with most ligands detecting copper (II) and cyanide ions, but with the capability to detect other metals such as iron, mercury, and cobalt as well.

Epithelial Cell Adhesion Molecule (EpCAM) Expression Can Be Modulated via NFκB.

The epithelial cell adhesion molecule (EpCAM) is considered an essential proliferation signature in cancer. In the current research study, qPCR induced expression of EpCAM was noted in acute lymphoblastic leukemia (ALL) cases. Costunolide, a sesquiterpene lactone found in crepe ginger and lettuce, is a medicinal herb with anticancer properties. Expression of EpCAM and its downstream target genes (Myc and TERT) wasdownregulated upon treatment with costunolide in Jurkat cells. A significant change in the telomere length of Jurkat cells was not noted at 72 h of costunolide treatment. An in silico study revealed hydrophobic interactions between EpCAM extracellular domain and Myc bHLH with costunolide. Reduced expression of NFκB, a transcription factor of EpCAM, Myc, and TERT in costunolide-treated Jurkat cells, suggested that costunolide inhibits gene expression by targeting NFκB and its downstream targets. Overall, the study proposes that costunolide could be a promising therapeutic biomolecule for leukemia.

In Silico and In Vitro Analysis of Helicobacter pullorum Type Six Secretory Protein Hcp and Its Role in Bacterial Invasion and Pathogenesis.

Helicobacter pullorum is a human zoonotic pathogen transmitted through poultry where it is associated with vibrionic hepatitis and colitis. Hemolysin co-regulated protein (Hcp) is an important structural as well as effector protein of type six secretory system; however, its role in H. pullorum invasion and pathogenesis has not been elucidated. In this study, we predicted the Helicobacter pullorum Hcp (HpuHcp) structure and identified Campylobacter jejuni Hcp (CjHcp) as its nearest homologue. Analysis of the predicted structure shows several common bacterial Hcp motifs like Protein kinase C phosphorylation site, Casein kinase II phosphorylation site, N-myristoylation site, cAMP-and cCGMP-dependent protein kinase phosphorylation site, N-glycosylation site. The presence of unique microbodies C-terminal targeting signal domain was present in HpuHcp which was seen for the first time in CjHcp. This could indicate that Hcp is a structural protein as well as a secretory protein. Moreover, the presence of a deamidase domain, similar to the tecA of Burkholderia cenocepacia an opportunistic pathogen, may help in bacterial internalization as it depolymerises the membranous actin by deamidation of the host cell Rho GTPases cdc42 and Rac1, which was supported by increased invasion of hepatocytes by Hcp-positive isolates.

In Silico and Ex Vivo Analyses of the Inhibitory Action of the Alzheimer Drug Posiphen and Primary Metabolites with Human Acetyl- and Butyrylcholinesterase Enzymes.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Ongoing research to develop AD treatments has characterized multiple drug targets including the cholinergic system, amyloid-ß peptide, phosphorylated tau, and neuroinflammation. These systems have the potential to interact to either drive or slow AD progression. Promising agents that simultaneously impact many of these drug targets are the AD experimental drug Posiphen and its enantiomer phenserine that, currently, are separately being evaluated in clinical trials. To define the cholinergic component of these agents, the anticholinesterase activities of a ligand dataset comprising Posiphen and primary metabolites ((+)-N1-norPosiphen, (+)-N8-norPosiphen, and (+)-N1,N8-bisnorPosiphen) were characterized and compared to those of the enantiomer phenserine. The "target" dataset involved the human cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Binding interactions between the ligands and targets were analyzed using Autodock 4.2. The computationally determined inhibitory action of these ligands was then compared to ex vivo laboratory-measured values versus human AChE and BChE. While Posiphen lacked AChE inhibitory action, its major and minor metabolites (+)-N1-norPosiphen and (+)-N1,N8-bisnorPosiphen, respectively, possessed modest AChE inhibitory activity, and Posiphen and all metabolites lacked BChE action. Phenserine, as a positive control, demonstrated AChE-selective inhibitory action. In light of AChE inhibitory action deriving from a major and minor Posiphen metabolite, current Posiphen clinical trials in AD and related disorders should additionally evaluate AChE inhibition; particularly if Posiphen should be combined with a known anticholinesterase, since this drug class is clinically approved and the standard of care for AD subjects, and excessive AChE inhibition may impact drug tolerability.

A strategy for mitigating avian colibacillosis disease using plant growth promoting rhizobacteria and green synthesized zinc oxide nanoparticles.

Avian colibacillosis caused by the zoonotic pathogen Escherichia coli is a common bacterial infection that causes major losses in the poultry sector. Extracts of different medicinal plants and antibiotics have been used against poultry bacterial pathogens. However, overuse of antibiotics and extracts against pathogenic strains leads to the proliferation of multi-drug resistant bacteria. Due to their environmentally friendly nature, nanotechnology and beneficial bacterial strains can be used as effective strategies against poultry infections. Green synthesis of zinc oxide nanoparticles (ZnO-NPs) from Eucalyptus globulus leaves was carried out in this study. Their characterization was done by UV-vis spectroscopy, X-ray diffraction (XRD), and Fourier transmission infrared spectroscopy (FT-IR) which confirmed their synthesis, structure, and size. In vitro, antimicrobial activities of plant leaf extract, ZnO-NPs, and plant growth-promoting rhizobacteria (PGPR) were checked against E. coli using well diffusion as well as disc diffusion method. Results proved that the antimicrobial activity of ZnO-NPs and PGPR strains was more enhanced when compared to eucalyptus leaf extract at 36 h. The maximum relative inhibition shown by ZnO-NPs, PGPR strains and eucalyptus leaf extracts was 88%, 67% and 58%, respectively. The effectiveness of ZnO-NPs was also increased with an increase in particle dose and treatment time. The 90 mg/ml of ZnO-NPs was more effective. PGPR strains from all over the tested strains, Pseudomonas sp. (HY8N) exhibited a strong antagonism against the E. coli strain as compared to other PGPR strains used in this study. However, combined application of PGPR (Pseudomonas sp. (HY8N)) and ZnO-NPs augment antagonistic effects and showed maximum 69% antagonism. The study intends to investigate the binding affinity of ZnO-NPs with the suitable receptor of the bacterial pathogen by in silico methods. The binding site conformations showed that the ligand ZnO binds with conserved binding site of penicillin-binding protein 6 (PBP 6) receptor. According to the interactions, ZnO-NPs form the same interaction pattern with respect to other reported ligands, hence it can play a significant role in the inhibition of PBP 6. This research also found that combining ZnO-NPs with Pseudomonas sp. (HY8N) was a novel and effective technique for treating pathogenic bacteria, including multidrug-resistant bacteria.

Synthesis, spectral analysis and biological evaluation of 2-{[(morpholin-4-yl)ethyl]thio}-5-phenyl/aryl-1,3,4-oxadiazole derivatives.

A series of new derivatives of 4-(2-chloroethyl)morpholine hydrochloride (5) were efficiently synthesized. Briefly, different aromatic organic acids (1a-f) were refluxed to acquire respective esters (2a-f) using conc. H2SO4 as catalyst. The esters were subjected to nucleophillic substitution by monohydrated hydrazine to acquire hydrazides (3a-f). The hydrazides were cyclized with CS2 in the presence of KOH to yield corresponding oxadiazoles (4a-f). Finally, the derivatives, 6a-f, were prepared by reacting oxadiazoles (4a-f) with 5 using NaH as activator. Structures of all the derivatives were elucidated through 1D-NMR EI-MS and IR spectral data. All these molecules were subjected to antibacterial and hemolytic activities and showed good antibacterial and hemolytic potential relative to the reference standards.

Scattering of Light from the Systemic Circulatory System.

There are many factors of methodological origin that influence the measurement of optical properties of the entire circulatory system which consists of blood as the basic component. The basic idea of this review article is to provide the optical properties of the circulatory system with all those factors of influence that have been employed in biomedical optics for different applications. We begin with the available optical properties, i.e., absorption, scattering and, reduced scattering coefficient, in general for any tissue inside the human body and prominent scattering theories (e.g., light, X-rays, neutrons) that are helpful in this regard. We have reviewed and compiled already available formulas and their respective available data for different human tissues for these optical properties. Then we have descended to the blood composition and to different scattering techniques available in the literature to study scattering and light propagation inside blood. We have reviewed both computational and theoretical scattering techniques.

Quality Of Sleep And Its Associated Factors Among Diabetics And Non Diabetics.

BACKGROUND: Diabetes mellitus is the metabolic state which has shown a persistent global rise in numbers. It is therefore necessary to closely assess all aspects of this state. Sleep quality and diabetic control have a relation where both can affect each other. Therefore, we aim to study the quality of sleep and factors affecting it in our diabetic population. The objective of the study was the identification of quality of sleep and factors affecting it in the diabetic and non diabetic adult population. METHODS: In this comparative cross sectional study quality of sleep was evaluated in all the patients through the Pittsburgh Sleep Quality Index. Statistical analysis was conducted with the SPSS-23. RESULTS: The total number of study participants were 250 adults (18 years and above), where 125 were diabetics, while 125 were non diabetics. In Diabetic group, the total number of patients with impaired sleep was 65 (52%). In non-diabetic group, impaired sleep was found in 70 (56%) individuals. The mean age of diabetics was 55.2±11.6 years and non-diabetics was 37.23±12.017 years. Prevalence of restless leg syndrome and depression among diabetics was 33 (26.4%) and 30 (24.0%) respectively and in nondiabetic was 20 (16.0%) and 63 (50.4%). Impaired sleep quality was associated with the use of cell phones before going to bed (p-value: 0.01) and watching television until late at night in both groups. Impaired sleep is seen more commonly in uncontrolled DM (RR:1.462 and CI: 0.531 to 4.025). CONCLUSIONS: Impaired sleep and uncontrolled DM has a direct relation and the prevalence of Restless leg syndrome (RLS) is higher in Diabetics. Addressing the factors impairing sleep can improve sleep quality and have beneficial effects on the sufferers from this metabolic state.

Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602.

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.

Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis.

PCSK9 (Proprotein convertase Subtilisin/Kexin Type 9), an important regulator of lipid metabolism, has been shown to play a role in hepatocellular carcinoma by promoting metastasis. PCSK9 interferes with LDL metabolism and causes dyslipidemias in hematological malignancies particularly acute lymphoblastic leukemia. Nutraceuticals like berberine, curcumin and polydatin have been found effective in modulating PCSK9 expression by lowering LDL levels. Eugenol, a nutraceutical has shown a promising role in cancer due to its antioxidant and antihypercholesterolemic effects. In the present study, PCSK9 expression was measured in acute lymphoblastic leukemia (ALL) patients and was found to be significantly induced. Based on the results of expression analysis, a plausible hypothesis was made. Eugenol being an antioxidant will prevent oxidation of LDL. In the absence of ox-LDL, LOX1 scavenger receptor, which regulates PCSK9 expression, will not be activated. As the circulating LDL is reduced, it will no longer be able to support leukemia cell growth. The hypothesis was validated by an in silico and in vitro study. Molecular docking revealed hydrophobic interactions between ligand eugenol and macromolecules PCSK9 and LOX1. Expression of both PCSK9 and LOX1 were significantly reduced by eugenol in Jurkat cells. To conclude, PCSK9 could therapeutically be targeted by eugenol in leukemia cells.

Computational Protein-Protein Docking Reveals the Therapeutic Potential of Kunitz-type Venom against hKv1.2 Binding Sites.

BACKGROUND & OBJECTIVE: Kunitz-type venoms are bioactive proteins isolated from a wide variety of venomous animals. These venoms are involved in protease inhibitory activity or potassium channel blocking activity. Therefore, they are reported as an important source for lead drug candidates towards protease or channel associated diseases like neurological, metabolic and cardiovascular disorders. METHODS: This study aimed to check the inhibitory action of Kunitz-type venoms against potassium channels using computational tools. RESULTS: Among potassium channels, Human Voltage-Gated Potassium Channel 1.2 (hKv1.2) was used as a receptor whereas Kunitz-type peptides from the venoms of various species were selected as ligand dataset. CONCLUSION: This study helped in finding the binding interface between the receptor and ligand dataset for their potential therapeutic use in treating potassium channelopathies.

Structure Activity Relationship of Venom Toxins Targeting Potassium Channels.

BACKGROUND: Peptide toxins are naturally occurring rich sources of highly specific bioactive compounds from venomous animals acting on various types of ion channels. OBJECTIVE: This study mainly highlights targeting of one of the largest families of ion channels i.e. potassium channels via venom toxins. METHOD: Data for reported venom toxins from diverse species is gathered and analyzed at sequence and structural extent. RESULTS: The similarities and differences among toxins have been demonstrated along with structure activity relationship of potassium channels with these toxins. CONCLUSION: This review highlights the importance of functionally important residues and structural scaffolds of venoms interacting with potassium channels.

In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA.

In humans, purine de novo synthesis pathway consists of multi-functional enzymes. Nucleotide metabolism enzymes are potential drug targets for treating cancer and autoimmune diseases. Glycinamide ribonucleotide transformylase (GART) is one of the most important trifunctional enzymes involved in purine synthesis. Previous studies have demonstrated the role of folate inhibitors against tumor activity. In this present study, three components of GART enzyme were targeted as receptor dataset and in silico analysis was carried out with folate ligand dataset. To accomplish the task, Autodock 4.2 was used for determining the docking compatibilities of ligand and receptor dataset. Taken together, it has been suggested that folate ligands could be potentially used as inhibitors of GART.

In silico analysis of binding interaction of conantokins with NMDA receptors for potential therapeutic use in Alzheimer's disease.

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptors are glutamate receptors that play vital roles in central nervous system development and are involved in synaptic plasticity, which is an essential process for learning and memory. The subunit N-methyl D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter receptor in the mammalian brain. Disturbances in the neurotransmission mediated by the NMDA receptor are caused by its overexposure to glutamate neurotransmitter and can be treated by its binding to an antagonist. Among several antagonists, conantokins from cone snails are reported to bind to NMDA receptors. METHODS: This study was designed to analyze the binding mode of conantokins with NMDA receptors in both humans and rats. To study interactions, dockings were performed using AutoDock 4.2 and their results were further analyzed using various computational tools. RESULTS: Detailed analyses revealed that these ligands can bind to active site residues of both receptors as reported in previous studies. CONCLUSIONS: In light of the present results, we suggest that these conantokins can act as antagonists of those receptors and play an important role in understanding the importance of inhibition of NMDA receptors for treatment of Alzheimer's disease.

In silico Analysis of AMP-activated Protein Kinase and Ligand-based Virtual Screening for Identification of Novel AMPK Activators.

BACKGROUND: Adenosine-Monophosphate-Activated protein kinase (AMPK) is a conserved kinase that plays an important role in maintaining the homeostasis of cells. AMPK activation has a positive impact on treatment of diseases such as diabetes, obesity and cancer as well. This observation led to the development of AMPK activators. Certain naturally occurring compounds have also been known to activate AMPK. METHODS: In this study, we retrieved the AMPK activators that include chemical drugs, xenobiotics and natural compounds and analyzed their interactions with AMPK via docking studies. Using this ligand dataset, a pharmacophore model was generated based upon ligand-based pharmacophore modeling strategy. The generated pharmacophore model was used to screen a library of ZINC database. The new hits which share the properties of our pharmacophore model were further analyzed via docking studies. RESULTS: This study led to the identification of new chemical compounds which has the potential to activate AMPK. Even some of the screened hits showed better binding energies as compared to that of the ligand dataset used thus having the potential to activate AMPK more efficiently. The promising hits obtained after virtual screening of ZINC database were also checked against the Lipinski's rule of five. CONCLUSION: Compound 7 out of the 10 compounds showed best binding energies even more efficient than the ligand dataset itself.

Comparative genomics study for identification of putative drug targets in Salmonella typhi Ty2.

Typhoid presents a major health concern in developing countries with an estimated annual infection rate of 21 million. The disease is caused by Salmonella typhi, a pathogenic bacterium acquiring multiple drug resistance. We aim to identify proteins that could prove to be putative drug targets in the genome of S. typhi str. Ty2. We employed comparative and subtractive genomics to identify targets that are absent in humans and are essential to S. typhi Ty2. We concluded that 46 proteins essential to pathogen are absent in the host genome. Filtration on the basis of drug target prioritization singled out 20 potentially therapeutic targets. Their absence in the host and specificity to S. typhi Ty2 makes them ideal targets for treating typhoid in Homo sapiens. 3D structures of two of the final target enzymes, MurA and MurB have been predicted via homology modeling which are then used for a docking study.

Pharmacophore-Based Virtual Screening for Identification of Novel Neuraminidase Inhibitors and Verification of Inhibitory Activity by Molecular Docking.

Oseltamivir and Zanamivir are two of the recently licensed neuraminidase inhibitors used for the treatment of influenza. However, alternative antiviral agents are needed due to the development of resistant mutations in Oseltamivir subtype H1N1 and H5N1 avian influenza A viruses, the latter being a highly pathogenic avian virus that can be transferred to humans upon immediate contact with H5N1 infected poultry or surface. Novel drug inhibiting group 1 neuraminidases may potentially be developed through addition of extra substituent moieties to existing inhibitor skeletons. Another approach involves virtual screening of existing inhibitor skeletons which we have reported using novel ligands of H5N1 via virtual screening approach. In this study, we have used 3D structure of avian influenza virus H5N1 neuraminidase as target against a ligand dataset of four known neuraminidase inhibitors for in silico analysis. Using the dataset of known four inhibitors, a pharmacophore model was developed using ligand-based pharmacophore modeling strategy. This pharmacophore model was then used for virtual screening of natural compounds library taken from Princeton database. New hits that shared features of our pharmacophore model and binding interactions with receptor residues have been reported in this study. As more antiviral agents are required, the reported hits in our study may play an important role as novel antiviral agents against influenza virus.

In Silico Analysis of Binding Interaction of Mamba Toxins with M4 and M2 Muscarinic Acetylcholine Receptors for Therapeutic Use in Alzheimer's Disease.

Muscarinic acetylcholine receptors are stimulated by the neurotransmitter acetylcholine and are involved in various functions across the human body. These receptors have surfaced for their potential use as targets in treatment of Alzheimer's disease. Muscarinic receptors have been reported to show binding interaction with various mamba toxins, such as dendrotoxins and muscarinic toxins that act as antagonists of these receptors. Therefore, in our study we have focused on the binding analysis of these mamba toxins with the M4 and M2 muscarinic acetylcholine autoreceptors for their potential use as targets in treating cognitive symptoms associated with Alzheimer's disease. A ligand dataset was developed that consisted of dendrotoxins and muscarinic toxins originating from various mamba species. Receptor dataset consisted of M4 and M2 muscarinic acetylcholine autoreceptors. Docking studies were performed using AutoDock 4.2 between these ligands with each receptor and further analysis was done using various computational tools. Docking experiments were performed and analyzed to check the binding compatibilities between mamba toxins and muscarinic acetylcholine autoreceptors. Detail analysis revealed that these ligands bind to active site residues of both receptors. Therefore by these in silico results, we suggest that the mamba toxins can be potential antagonists of the M4 and M2 muscarinic acetylcholine autoreceptors.