Synthesis, crystal structure, Hirshfeld surface analysis, DFT, molecular docking and molecular dynamic simulation studies of (E)-2,6-bis(4-chlorophenyl)-3-methyl-4-(2-(2,4,6-trichlorophenyl)hydrazono)piperidine derivatives.

A novel drug to treat SARS-CoV-2 infections and hydroxyl chloroquine analogue, (E)-2,6-bis(4-chlorophenyl)-3-methyl-4-(2-(2,4,6-trichlorophenyl)hydrazono)piperidine (BCMTP) compound has been synthesized in one pot reaction. The novel compound BCMTP has been characterized by FT-IR, 1H-NMR, 13C-NMR and single-crystal X-ray diffraction patterns. Crystal packing is stabilized by C8-H8A•••Cl10i, C41-H41•••Cl1ii and N1-H1A•••Cl6iii intermolecular hydrogen bonds. From the geometrical parameters, it is observed that the piperidine ring adopts chair conformation. Hirshfeld surface analysis was carried out to quantify the interactions and an interaction energy analysis was done to study the interactions between pairs of molecules. The geometrical structure was optimized by density functional theory (DFT) method at B3LYP/6-31G (d, p) as the basic set. The smaller binding energy value provides the higher reactivity of BCMTP compound than hydroxyl chloroquine and was corrected by high electrophilic and low nucleophilic reactions. The stability and charge delocalization of the molecule were also considered by natural bond orbital (NBO) analysis. The HOMO-LUMO energies describe the charge transfer which takes place within the molecule. Molecular electrostatic potential has also been analysed. Molecular docking studies are implemented to analyse the binding energy of the BCMTP compound against standard drugs such as the crystal structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES and SARS-CoV-2 main protease with an unliganded active site (2019-nCoV, corona virus disease 2019, COVID-19) and found to be considered having better antiviral agents. Molecular dynamics simulation was performed for COVID-19 main protease (Mpro: 6WCF/6Y84) to understand the elements governing the inhibitory effect and the stability of interaction under dynamic conditions.

Molecular Docking of Seaweed-Derived Drug Fucoxanthin Against the Monkeypox Virus.

Background The monkeypox virus (MPXV) is classified as a zoonotic virus of the Poxviridae family, resulting from the MPXV strain of the Orthopoxvirus genus. Seaweeds, or marine macroalgae, are abundant reservoirs of bioactive compounds that demonstrate diverse biological properties, such as antiviral actions. In the field of computational analysis, in silico analysis refers to the use of computer-based methods to study and assess biological systems and processes. To forecast the binding affinity and interaction between the discovered chemical and the target proteins of the MPXV, a molecular docking analysis was conducted. Aim The research aims to conduct an in silico examination of a protein-ligand interaction of a drug produced from seaweed that targets the MPXV.  Methodology Protein Data Bank (PDB) and PubChem databases provided MPXV methyltransferase and fucoxanthin ligand compounds. AutoDockTools 1.5.7 calculated the molecular docking using the Lamarckian genetic algorithm. Autogrid created a grid box around target 8B07 active site hotspot residues. Each docked molecule's docking parameters were obtained from 100 docking experiments with a maximum of 2.5 × 106 energy evaluations, a 0.02 mutation rate, and a 0.8 crossover rate. The population comprised 250 randomly selected volunteers. PyMOL was utilized to observe ligand fragment interactions. Results The binding energy of the ligand fucoxanthin was -5.46 kcal/mol. Fucoxanthin interacts with receptor molecules via hydrogen bonding at the amino acid level: Chain A: PHE188 and TYR189; and Chain B: LYS33, GLN37, GLY38, GLY96, ARG97, PHE115, PRO202, and SER203. The higher the negative docking score, the stronger the binding affinity between the receptor and ligand molecules, indicating that bioactive substances are more effective. Conclusion The findings of this study indicate that fucoxanthin, a pharmaceutical derivative generated from seaweed, had antiviral activity against the MPXV. This conclusion was reached based on protein-ligand interactions.

Decoding the mechanism of andrographolide to combat hepatocellular carcinoma: a network pharmacology integrated molecular docking and dynamics approach.

HepatoCellular Carcinoma, being one of the most mortally convoluted malignancy with mounting number of occurrences across the world and being classified as the third most prevalent cause of cancer-associated mortalities and sixth most prevalent neoplasia. The active phytoconstituent andrographolide, derived from Andrographis paniculata is conveyed to reconcile a number of human ailments including various oncologies. However, the molecular mechanism underlying the anti-oncogenic effects of Andrographolide on HCC remains skeptical and unclear, emerging as a budding challenge for researchers and oncologists. The present study intends to analyze the underlying pharmacological mechanism of Andrographolide over HCC, established via assimilated approach of network pharmacology. Herein, the Network pharmacology stratagem was instigated to investigate potential HCC targets. The Andrographolide targets along with HCC targets were extracted from multiple databases. A total of 162 potential overlapping targets among HCC and Andrographolide were obtained and further subjected to gene ontology and Pathway enrichment analysis by employing OmicsBox and DAVID database, respectively. Subsequently, Protein-protein interaction network construction by Cytoscape software identified the top 10 hub nodes which were validated by survival and expression analysis. Further, the results derived from molecular docking and dynamic simulations by CB-Dock2 server and Desmond module (Schrodinger software) indicate ALB, CCND1, HIF1A, TNF, and VEGFA as potential Andrographolide related targets with high binding affinity and promising complex stability. Our findings not only reveal the antioncogenic role of andrographolide but also provide novel insights illuminating the identified targets as scientific foundation for anti-oncogenic clinical application of andrographolide in HCC therapeutics.Communicated by Ramaswamy H. Sarma.

Berberine chloride (dual topoisomerase I and II inhibitor) modulate mitochondrial uncoupling protein (UCP1) in molecular docking and dynamic with in-vitro cytotoxic and mitochondrial ATP production.

Obesity initiates numerous diseases like cardiovascular, metabolic, and type 2 diabetes, and obesity is a vital cause of death worldwide. Plants are necessary to the source of life. Several drug compounds isolated from plants are called phytochemicals which are safe, effective drug moieties to treat several diseases. Berberine chloride is a dual topoisomerase I and II inhibitor, that exhibited potent antitumor activities against several malignancies. However, the effect of Berberine on mitochondria remains unknown. The focus of this study was to determine the role of Berberine on mitochondrial uncoupling protein (UCP1), ATP production, and cytotoxic effect of HEK293T cell at a time and dose-dependent manner analysis by CCK8 assay. The upregulation of mitochondrial UCP1 gene expression reduces adipocyte content by initiating thermogenesis. In this study, berberine chloride significantly up-regulates UCP1 gene expression in brown adipocytes. AT 10 µM concentration of Berberine 48 h treatment demonstrated significant cell death. The decreased level of ATP production leads to mitochondrial uncoupling. Initiate thermogenesis reducing fat droplets in adipocytes. The first time, we used molecular docking and dynamic of Berberine with UCP1 gene in this study and revealed therapeutic potential of Berberine via modulation of mitochondrial UCP1 gene. Further investigation will reveal new insight into mechanisms to treat metabolic-related diseases.Communicated by Ramaswamy H. Sarma.

Profiling the antidiabetic potential of GC-MS compounds identified from the methanolic extract of Spilanthes filicaulis: experimental and computational insight.

This study examines the nutritional composition, phytochemical profiling, and antioxidant, antidiabetic, and anti-inflammatory potential of a methanolic extract of Spilanthes filicaulis leaves (MESFL) via in vitro, ex vivo, and in silico studies. In vitro antioxidant, antidiabetic, and anti-inflammatory activities were examined. In the ex vivo study, liver tissues were subjected to FeSO4-induced oxidative damage and treated with varying concentrations of MESFL. MESFL contains a reasonable amount of nitrogen-free extract, moisture, ash content, crude protein, and fat, with a lesser amount of crude fiber. According to GC-MS analysis, MESFL contains ten compounds, the most abundant of which are 13-octadecenal and Ar-tumerone. In this study, MESFL demonstrated anti-inflammatory activities via membrane stabilizing properties, proteinase inhibition, and inhibition of protein denaturation (IC50 = 72.75 ± 11.06 µg/mL). MESFL also strongly inhibited both α-amylase (IC50 = 307.02 ± 4.25 µg/mL) and α-glucosidase (IC50 = 215.51 ± 0.47 µg/mL) activities. Our findings also showed that FeSO4-induced tissue damage decreased the levels of GSH, SOD, and CAT activities while increasing the levels of MDA. In contrast, treatment with MESFL helped to restore these parameters to near-normal levels, which signifies that MESFL has great potential to address complications from oxidative stress. Furthermore, the in silico interaction of the GCMS-identified phytochemicals with the active sites of α-amylase and α-glucosidase via molecular and ensembled-based docking displayed strong binding affinities of Ar-tumerone and 4-hydroxy-3-methylacetophenone to α-amylase and α-glucosidase, respectively. Taken together, the biological activities of MESFL might be a result of the effects of these secondary metabolites.Communicated by Ramaswamy H. Sarma.

Solvent Free Twin Screw Processed Silybin Nanophytophospholipid: In Silico, In Vitro and In Vivo Insights.

Silybin (SIL) is a polyphenolic phytoconstituent that is commonly used to treat liver disorders. It is difficult to fabricate an orally delivered SIL product due to its low oral bioavailability (0.95%). Therefore, the current research focusses on the development of a novel composition of a phospholipid complex, termed as nanophytophospholipid, of SIL by employing a unique, solvent-free Twin Screw Process (TSP), with the goal of augmenting the solubility and bioavailability of SIL. The optimised SIL-nanophytophospholipid (H6-SNP) was subjected to physicochemical interactions by spectrometry, thermal, X-ray and electron microscopy. The mechanism of drug and phospholipid interaction was confirmed by molecular docking and dynamics studies. Saturation solubility, in vitro dissolution, ex vivo permeation and preclinical pharmacokinetic studies were also conducted. H6-SNP showed good complexation efficiency, with a high practical yield (80%). The low particle size (334.7 ± 3.0 nm) and positively charged zeta potential (30.21 ± 0.3 mV) indicated the immediate dispersive nature of H6-SNP into nanometric dimensions, with good physical stability. Further high solubility and high drug release from the H6-SNP was also observed. The superiority of the H6-SNP was demonstrated in the ex vivo and preclinical pharmacokinetic studies, displaying enhanced apparent permeability (2.45-fold) and enhanced bioavailability (1.28-fold). Overall, these findings indicate that not only can phospholipid complexes be formed using solvent-free TSP, but also that nanophytophospholipids can be formed by using a specific quantity of lipid, drug, surfactant, superdisintegrant and diluent. This amalgamation of technology and unique composition can improve the oral bioavailability of poorly soluble and permeable phytoconstituents or drugs.

Schizandrin A exhibits potent anticancer activity in colorectal cancer cells by inhibiting heat shock factor 1.

Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.