Isolation, chemical characterization, antimicrobial activity, and molecular docking studies of 2,6-dimethoxy benzoquinone isolated from medicinal plant Flacourtia jangomas.

In the present investigation one compound, 2,6-dimethoxy benzoquinone (FJL-1), was isolated from the dichloromethane (DCM) fraction of the organic leaf extract of Flacourtia Jangomas for the first time. The compound structure was elucidated using extensive spectral analysis, including 1H, and 13C NMR. Furthermore, the DPPH and ABTS methods were used to evaluate the antioxidant activity of the organic extract, its fractions, and the isolated compound FJL-1. Antioxidant activity of the petroleum, ether, DCM, and methanol fractions of the organic extract and the isolated compound of F. Jangomas revealed moderate to strong radical scavenging ability. Additionally, the antimicrobial activity of FJL-1 against Staphylococcus aureus (MTCC 737 and MTCC 96 strains) was observed in an inhibition zone size of 21.6 ± 0.6 to 21.7 ± 0.58 mm showing potential inhibitory activity. The isolated compound FJL-1 shows excellent binding with the 2W9S proteins in terms of docking score compared with the drug Trimethoprim, which also exhibited similar types of interaction and potency against S. aureus. The leaves of F. jangomas can be considered a great source for the identification of numerous important phytoconstituents with potential uses in nutrition, aromatherapy, and the pharmaceutical sector. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04002-w.

GC-MS fingerprinting, nutritional composition, in vitro pharmacological activities and molecular docking studies of Piper chaba from Uttarakhand region.

This study aimed to evaluate the potential therapeutic effects of Piper chaba (PC) growing in the northern region of India, having differences in the phytochemicals, nutritional content, antimicrobial and antioxidant properties by reducing power assay (RPA), 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, phosphomolybdate assay, and antidiabetic potential by α-amylase assay with change in the geographical location. Outcomes of the gas chromatography-mass spectrometry (GC-MS) analysis revealed that phytochemicals such as piperine (46.69%), kusunokinin (8.9%), and sitostenone (7.57%) are the prominent compounds found in PC. The plant has also shown a good nutritional value, i.e., iron (11.25 mg), calcium (147 mg), and vitamin C (9.30 mg) per 100 g. PC has a higher phenolic content than other species (⁓ 13.75 g/100 g plant powder). Among the four tested bacterial strains, the extract is best responsive toward Escherichia coli (35 ± 0.68 mm) which is more than the standard ciprofloxacin (24 ± 0.8 mm). Similarly, among two tested fungal strains, Saccharomyces cerevisiae shows the best zone of inhibition (ZOI) (27.5 ± 0.8 mm), which is greater than tat of standard amphotericin (20.25 ± 0.28 mm). The DDPH method demonstrated the highest antioxidant activity (⁓ 42.61 ± 1.82 µg/ml). IC50 for the antidiabetic potential of PC was found to be 23.09 ± 0.3 µg/ml against α-amylase assay. A molecular docking study revealed that three compounds, piperine, sitostenone and kusunokinin, showed strong binding affinity toward bacterial tyrosyl-tRNA synthetases, fungal dihydrofolate reductase, and α-amylase, respectively. Therefore, the findings of the current study indicate that PC can be considered as a source of food and medicines, either in the form of traditional preparations or as pure active constituents. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03996-7.

In silico guided screening of active components of C. lanceolata as 3-chymotrypsin-like protease inhibitors of novel coronavirus.

Despite the intense worldwide efforts towards the identification of potential anti-CoV therapeutics, no antiviral drugs have yet been discovered. Numerous vaccines are now approved for use, but they all serve as preventative measures. To effectively treat viral infections, it is crucial to find new antiviral drugs that are derived from natural sources. Various compounds with potential activity against 3 chymotrypsin-like protease (3CLpro) were reported and some are validated by bioassay studies. Therefore, we performed the computational screening of phytoconstituents of Codonopsis lanceolata to search for potential antiviral hit candidates. The curated compounds of the plant C. lanceolata were collected and downloaded from the literature. The binding affinity of the curated datasets was predicted for the target 3CLpro. Stigmasterol exhibits the highest docking score for the 3CLpro target. In addition, molecular dynamics (MD) simulations were conducted for the validation of docking results using root mean square deviation and root mean square fluctuation plots. The MD results indicated that the docked complex was stable and retained hydrogen bonding and non-bonding interactions. Furthermore, the calculation of pharmacokinetic parameters and Lipinski's rule of five suggest that C. lanceolata has the potential for drug-likeness. In order to develop new medicines for this debilitating disease, we will focus on the primary virus-based and host-based targets that can direct medicinal chemists to identify novel treatments to produce new drugs for it. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03745-2.

Lactate acidosis and simultaneous recruitment of TGF-ß leads to alter plasticity of hypoxic cancer cells in tumor microenvironment.

Lactate acidosis is often observed in the tumor microenvironment (TME) of solid tumors. This is because glucose breaks down quickly via glycolysis, causing lactate acidity. Lactate is harmful to healthy cells, but is a major oncometabolite for solid cancer cells that do not receive sufficient oxygen. As an oncometabolite, it helps tumor cells perform different functions, which helps solid hypoxic tumor cells spread to other parts of the body. Studies have shown that the acidic TME contains VEGF, Matrix metalloproteinases (MMPs), cathepsins, and transforming growth factor-ß (TGF-ß), all of which help spread in direct and indirect ways. Although each cytokine is important in its own manner in the TME, TGF-ß has received much attention for its role in metastatic transformation. Several studies have shown that lactate acidosis can cause TGF-ß expression in solid hypoxic cancers. TGF-ß has also been reported to increase the production of fatty acids, making cells more resistant to treatment. TGF-ß has also been shown to control the expression of VEGF and MMPs, which helps solid hypoxic tumors become more aggressive by helping them spread and create new blood vessels through an unknown process. The role of TGF-ß under physiological conditions has been described previously. In this study, we examined the role of TGF-ß, which is induced by lactate acidosis, in the spread of solid hypoxic cancer cells. We also found that TGF-ß and lactate work together to boost fatty acid production, which helps angiogenesis and invasiveness.

Purification of ursolic acid and ß-sitosterol from endophytic Alternaria alternata for their alpha-amylase inhibitory activity.

Fungal endophytes are a known warehouse of bioactive compounds with multifarious applications. In the present investigation two compounds, ß-Sitosterol (1) and ursolic acid (2), were isolated from Alternaria alternata, an endophytic fungus associated with Morus alba Linn for the first time. The structure of the compounds was elucidated on the basis of comprehensive spectral analysis (UV, IR, 1 H-, 13 C- and 2D-NMR, as well as HRESI-MS). In the in vitro alpha amylase inhibitory assay both compounds (1) and (2) show potent antidiabetic activity. In support, Docking studies indicate significant binding affinity of the isolated compounds. Hence from the present study, it can be concluded that endophytic fungi in Morus alba Linn can find use in antidiabetic drug development in the medicinal industry.Communicated by Ramaswamy H. Sarma.

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival.

It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programme the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate associated bimodal regulations of TME.

Identification of potential inhibitors of Zika virus targeting NS3 helicase using molecular dynamics simulations and DFT studies.

Despite the various research efforts towards the drug discovery program for Zika virus treatment, no antiviral drugs or vaccines have yet been discovered. The spread of the mosquito vector and ZIKV infection exposure is expected to accelerate globally due to continuing global travel. The NS3-Hel is a non-structural protein part and involved in different functions such as polyprotein processing, genome replication, etc. It makes an NS3-Hel protein an attractive target for designing novel drugs for ZIKV treatment. This investigation identifies the novel, potent ZIKV inhibitors by virtual screening and elucidates the binding pattern using molecular docking and molecular dynamics simulation studies. The molecular dynamics simulation results indicate dynamic stability between protein and ligand complexes, and the structures keep significantly unchanged at the binding site during the simulation period. All inhibitors found within the acceptable range having drug-likeness properties. The synthetic feasibility score suggests that all screened inhibitors can be easily synthesizable. Therefore, possible inhibitors obtained from this study can be considered a potential inhibitor for NS3 Hel, and further, it could be provided as a lead for drug development.

Molecular Insights of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole as CRF-1 Receptor Antagonists: Combined QSAR, Glide Docking, Molecular Dynamics, and In-silico ADME Studies.

Stress-dependent disorders cause severe harm to human health and trigger the risk of neurodegenerative disorder. Corticotropin-releasing factor-1 receptor was found to be a potent drug target.We evaluate the essential structural residues for pharmacophore identification through 2D and 3D QSAR analysis and identify the binding residues for a possible mechanism of CRF-1 binding with 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives through molecular docking and molecular dynamics simulations. The best 2D QSAR model was obtained through the MLR method with an r2 value of 0.8039 and a q2 value of 0.6311. Also,a 3D QSAR model was generated through the KNN MFA method with a q2 value of 0.6013 and a q2_se value of 0.3167. Further, docking analysis revealed that residue Glu196 and Lys334 were involved in hydrogen bonding and Trp9 in Π- Π stacking. Simulation analysis proves that target protein interactions with ligands were stable, and changes were acceptable for small and globular proteins. Compound B18, a benzimidazole derivative, has an excellent binding affinity towards CRF-1 protein compared to reference molecules; hence, this compound could be a potential drug candidate for stress-dependent disorders. Based on findings, 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives could be a novel class of corticotropin-releasing factor 1 receptor antagonists for stress-related disorders. All benzimidazole derivatives were found to be within the acceptable range of physicochemical properties. Hence, these observations could provide valuable information for the design and development of novel and potent CRF-1 receptor antagonists.