Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy.

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aβ aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (- were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation.

Exploring the interaction of tepotinib with calf thymus DNA using molecular dynamics simulation and multispectroscopic techniques.

In recent times, there has been a surge in the discovery of drugs that directly interact with DNA, influencing gene expression. As a result, understanding how biomolecules interact with DNA has become a major area of research. One such drug is Tepotinib (TPT), an FDA-approved anti-cancer medication known as a MET tyrosine kinase inhibitor, used in chemotherapy for metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations.

Computational and physicochemical insight into 4-hydroxy-2-nonenal induced structural and functional perturbations in human low-density lipoprotein.

Lipid peroxidation (LPO) is a biological process that frequently occurs under physiological conditions. Undue oxidative stress increases the level of LPO; which may further contribute to the development of cancer. 4-Hydroxy-2-nonenal (HNE), one of the principal by-products of LPO, is present in high concentrations in oxidatively stressed cells.

Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization.

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by H & C NMR and mass spectrometry.

Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting proteins.

Stability of the Aβ42 Peptide in Mixed Solutions of Denaturants and Proline.

Amyloid β-peptide (Aβ) is responsible for the neuronal damage and death of a patient with Alzheimer's disease (AD). Aβ42 oligomeric forms are dominant neurotoxins and are related to neurodegeneration. Their different forms are related to various pathological conditions in the brain.

Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents.

Objective: Neuroprotection is a precise target for the treatment of neurodegenerative diseases, ischemic stroke, and traumatic brain injury. Pyrimidine and its derivatives have been proven to use antiviral, anticancer, antioxidant, and antimicrobial activity prompting us to study the neuroprotection and anti-inflammatory activity of the triazole-pyrimidine hybrid on human microglia and neuronal cell model.

Methods: A series of novel triazole-pyrimidine-based compounds were designed, synthesized and characterized by mass spectra, 1HNMR, 13CNMR, and a single X-Ray diffraction analysis.

Differential role of Pax6 and its interaction with Shh-Gli1-IDH2 axis in regulation of glioma growth and chemoresistance.

Glioma is a major brain tumor, and the associated mortality rate is very high. Contemporary therapies provide a chance of survival for 9-12 months. Therefore, a novel approach is essential to improve the survival rate.

-Guggulsterone Is a Potential Lead Molecule of Dawa-ul-Kurkum against Hepatocellular Carcinoma.

An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them.

In silico studies of the human IAPP in the presence of osmolytes.

The human islet amyloid polypeptide or amylin is secreted along with insulin by pancreatic islets. Under the drastic environmental conditions, amylin can aggregate to form amyloid fibrils. This amyloid plaque of hIAPP in the pancreatic cells is the cause of type II diabetes.

The inhibitory effect of Sunset Yellow on thermally induced Human Serum Albumin aggregates: Possible role in naturopathy.

Intensive research in the field of protein aggregation confirmed that the deposition of amyloid fibrils of proteins are the major cause for the development of various neurotoxic and neurodegenerative diseases, which could be controlled by ensuring the efficient inhibition of aggregation using anti aggregation strategies. Herein, we elaborated the anti amyloidogenic potential of Sunset Yellow (SY) dye against Human Serum Albumin (HSA) fibrillogenesis utilising different biophysical, computational and microscopic techniques. The inhibitory effect of sunset yellow was confirmed by Rayleigh Light Scattering (RLS) measurements along with different dye binding assays (ANS, ThT and CR) by showing concentration dependent reduction in scattering intensity and fluorescence intensity respectively.

Studying the interaction of scopolamine with calf-thymus DNA: An in-vitro and in-silico approach and genotoxicity.

Scopolamine is used to treat various CNS disorder like urinary incontinence, motion sickness, spasmic movements. Despite its pharmaceutical properties, its interaction with DNA is not yet reported. In this article, the interaction between scopolamine and ct-DNA is reported using a combination of biophysical techniques.

Biophysical characterization of structural and conformational changes in methylmethane sulfonate modified DNA leading to the frizzled backbone structure and strand breaks in DNA.

Methyl methanesulfonate (MMS) is a highly toxic DNA-alkylating agent that has a potential to damage the structural integrity of DNA. This work employed multiple biophysical and computational methods to report the MMS mediated structural alterations in the DNA (MMS-DNA). Spectroscopic techniques and gel electrophoresis studies revealed MMS induced exposure of chromophoric groups of DNA; methylation mediated anti→syn conformational change, DNA fragmentation and reduced nucleic acid stability.

Biophysical insight into the binding mechanism of doxofylline to bovine serum albumin: An in vitro and in silico approach.

Insight into the mechanistic binding of bovine serum albumin (BSA) with doxofylline can layout pivotal enlightenment with relevance to pharmacokinetics and pharmacodynamics properties. Herein, many spectroscopic techniques and computational methods had been employed to interpret the structural and binding dynamics of BSA-doxofylline interaction. Doxofylline quenched the intrinsic fluorescence of BSA by static quenching.

Effect of TMAO and Urea on Dimers and Tetramers of Amyloidogenic Heptapeptides (FGAILSS).

Human islet amyloid polypeptide (hIAPP) (1-37) is an intrinsically disordered protein that is released with insulin by β-cells found in the pancreas. Under certain environmental conditions, hIAPP can aggregate, which leads to β-cell death. FGAILSS (23-29) residues of the hIAPP protein form β sheets, which may be toxic species in type 2 diabetes (T2D) patients.

Stimulation of GMP formation in hGBP1 is mediated by W79 and its effect on the antiviral activity.

Interferon-inducible large GTPases are critical for innate immunity. The distinctive feature of a large GTPase, human guanylate binding protein-1 (hGBP1), is the sequential hydrolysis of GTP into GMP via GDP. Despite several structural and biochemical studies, the underlying mechanism of assembly-stimulated GMP formation by hGBP1 and its role in immunity are not fully clarified.

Interaction of memantine with calf thymus DNA: an and approach and cytotoxic effect on the cancerous cell lines.

Memantine belongs to the class of cognition enhancers that functions as NMDA receptor antagonist, used to treat Alzheimer's disease. The interaction of memantine with DNA was not investigated. In the present study, the interaction of memantine with ct-DNA, as well as its cytotoxicity on cancer cells, was evaluated.

Conformational dynamics of superoxide dismutase (SOD1) in osmolytes: a molecular dynamics simulation study.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the misfolding of Cu, Zn superoxide dismutase (SOD1). Several earlier studies have shown that monomeric apo SOD1 undergoes significant local unfolding dynamics and is the predecessor for aggregation. Here, we have employed atomistic molecular dynamics (MD) simulations to study the structure and dynamics of monomeric apo and holo SOD1 in water, aqueous urea and aqueous urea-TMAO (trimethylamine oxide) solutions.

Effect of syringic acid and syringaldehyde on oxidative stress and inflammatory status in peripheral blood mononuclear cells from patients of myocardial infarction.

Oxidative stress and inflammation are considered as therapeutic targets in myocardial injury. The aim of the present study was to investigate the protective effect of syringic acid (SA) and syringaldehyde (SYD) on peripheral blood mononuclear cells (PBMCs) of myocardial infarction (MI) patients. PBMCs from MI patients were cultured in the presence and absence of SA and SYD.

Effect of Osmolytes on Conformational Behavior of Intrinsically Disordered Protein α-Synuclein.

α-Synuclein is an intrinsically disordered protein whose function in a healthy brain is poorly understood. It is genetically and neuropathologically linked to Parkinson's disease (PD). PD is manifested after the accumulation of plaques of α-synuclein aggregates in the brain cells.

Effect of Urea, Arginine, and Ethanol Concentration on Aggregation of CVNITV Fragment of Sheep Prion Protein.

Understanding protein aggregation is of utmost importance as it is responsible for causing several neurodegenerative diseases and one of the serious impediments in large-scale biopharmaceutical production. The prion protein is responsible for pathological states in fatal transmissible spongiform conditions, such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. The peptide fragment 178-191 of Syrian hamster prion protein is known to be amyloidogenic.

Identification of small molecule inhibitors of ALK2: a virtual screening, density functional theory, and molecular dynamics simulations study.

Bone morphogenetic proteins (BMPs) are a family of more than 30 ligands and several receptors, such as activin like kinases (ALKs) and bone morphogenetic protein receptor (BMPR). Physiological significance of these proteins lies in their prominent role during homeostasis, apoptosis, tissue remodeling, embryonic patterning, and normal development. Fibrodysplasia ossificans progressive (FOP) is one among several other diseases caused by impaired BMP signaling.

Correlating interfacial water dynamics with protein-protein interaction in complex of GDF-5 and BMPRI receptors.

GDF-5 mediated signal transduction regulating chondrogenesis and skeletogenesis involves three different type-I receptors viz. Act-RI, BMPRIA and BMPRIB. BMPRIA and BMPRIB generally shows temporal and spatial co-expression but some spatially different expression pattern has also been observed.

Biophysical and biochemical studies on glycoxidatively modified human low density lipoprotein.

Methylglyoxal (MGO), a reactive dicarbonyl metabolite is a potent arginine directed glycating agent which has implications for diabetes-related complications. Dicarbonyl metabolites are produced endogenously and in a state of misbalance, they contribute to cell and tissue dysfunction through protein and DNA modifications causing dicarbonyl stress. MGO is detoxified by glyoxalase 1 (GLO1) system in the cytoplasm.