Exploring the neuropharmacological properties of scopoletin-rich Evolvulus alsinoides extract using in-silico and in-vitro methods.

OBJECTIVES: This study investigates the neuropharmacologic properties of Scopoletin, a bioactive compound in Evolvulus alsinoides (EA) extract, for managing cognitive impairment using in-vitro, in-silico, and zebrafish embryo toxicity assays. METHODS: The study estimates Scopoletin concentration in EA extract using HPTLC, assesses antioxidant properties using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing ability of plasma (FRAP) assays, and uses bioinformatic tools for scopoletin targets. Zebrafish embryo toxicity (ZET) is used to assess its toxicological profile. RESULTS: 0.0076% w/w Scopoletin in the samples was quantified using HPTLC, further studies on the DPPH (0.5 mM) and FRAP gave EC50 at 440.0 µg/ml and 84.29 µg/ml respectively. Twelve common targets associated with cognitive impairment (CI) were identified, along with possible pathways and molecular interactions. Our results indicate significant binding affinities of Scopoletin with ERAP1, SCN3A, and COMT. Molecular dynamics simulations further confirm the stability of these interactions. ZET assessment demonstrated mortality after 450 µg/ml concentration of EA extract. CONCLUSION: The study verifies the presence of Scopoletin in EA, along with their targets playing a crucial role in neurogenesis and neuroplasticity. The ZET demonstrated concentration-dependent effects, emphasizing the importance of dosage considerations in developing new formulations or therapeutics. This comprehensive study contributes valuable insight into the therapeutic potential of Scopoletin from EA for cognitive impairment, paving the way for further research.

Investigating multifaceted action of ibuprofen derivatives towards cox isozymes and interleukin-6 (IL-6) site correlating with various target sites.

The multifaceted action of new ibuprofen analogs has been investigated against inflammation, neurological and pro-inflammation factors. On the basis of ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, molecular docking as well as molecular dynamics simulation, compound 3 was thought to have good anti-inflammatory activity. As the presence of structural interactions such as conventional hydrogen bonds and electrostatic interactions through the nitrogen atoms of the linker in compound 3 gave strong evidence of its potency. The major finding of the current work is that the presence of appropriate number of hetero atoms (NH, OH) in a compound makes it more efficient than the number of labile groups (i.e., hydroxyl groups). Additionally, the position of hetero atoms in a compound and orientation also play a vital role in its efficacy. It was also screened for in vitro anti-inflammatory activity by membrane stability method, where it has shown 90.8% protection of RBC hemolysis. Thus, compound 3 with effective structural features may have good anti-inflammatory activity.Communicated by Ramaswamy H. Sarma.

Identification and evaluation of quercetin as a potential inhibitor of naphthoate synthase from Enterococcus faecalis.

Enterococcus faecalis is a gram-positive, rod-shape bacteria responsible for around 65% to 80% of all enterococcal nosocomial infections. It is multidrug resistant (MDR) bacterium resistant to most of the first-line antibiotics. Due to the emergence of MDR strains, there is an urgent need to find novel targets to develop new antibacterial drugs against E. faecalis. In this regard, we have identified naphthoate synthase (1,4-dihydroxy-2-naphthoyl-CoA synthase, EC: 4.1.3.36; DHNS) as an anti-E. faecalis target, as it is an essential enzyme for menaquinone (vitamin K2 ) synthetic pathway in the bacterium. Thus, inhibiting naphtholate synthase may consequently inhibit the bacteria's growth. In this regard, we report here cloning, expression, purification, and preliminary structural studies of naphthoate synthase along with in silico modeling, molecular dynamic simulation of the model and docking studies of naphthoate synthase with quercetin, a plant alkaloid. Biochemical studies have indicated quercetin, a plant flavonoid as the potential lead compound to inhibit catalytic activity of EfDHNS. Quercetin binding has also been validated by spectrofluorimetric studies in order to confirm the bindings of the ligand compound with EfDHNS at ultralow concentrations. Reported studies may provide a base for structure-based drug development of antimicrobial compounds against E. faecalis.

Molecular modeling and structure-based drug discovery approach reveals protein kinases as off-targets for novel anticancer drug RH1.

Potential drug target identification and mechanism of action is an important step in drug discovery process, which can be achieved by biochemical methods, genetic interactions or computational conjectures. Sometimes more than one approach is implemented to mine out the potential drug target and characterize the on-target or off-target effects. A novel anticancer agent RH1 is designed as pro-drug to be activated by NQO1, an enzyme overexpressed in many types of tumors. However, increasing data show that RH1 can affect cells in NQO1-independent fashion. Here, we implemented the bioinformatics approach of modeling and molecular docking for search of RH1 targets among protein kinase species. We have examined 129 protein kinases in total where 96 protein kinases are in complexes with their inhibitor, 11 kinases were in the unbound state with any ligand and for 22 protein kinases 3D structure were modeled. Comparison of calculated free energy of binding of RH1 with indigenous kinase inhibitors binding efficiency as well as alignment of their pharmacophoric maps let us predict and ranked protein kinases such as KIT, CDK2, CDK6, MAPK1, NEK2 and others as the most prominent off-targets of RH1. Our finding opens new avenues in search of protein targets that might be responsible for curing cancer by new promising drug RH1 in NQO1-independent way.

Design, synthesis and molecular modeling studies of few chalcone analogues of benzimidazole for epidermal growth factor receptor inhibitor in search of useful anticancer agent.

In the present investigation, few 3-(substitutedphenyl)-1-[2-(1-hydroxy-ethyl)]-1H-benzimidazol-1-yl)prop-2-en-1-ones are EGFR antagonist are designed, by molecular docking analysis. The synthesized compounds were tested for their in vitro anticancer activity by propidium iodide fluorescent assay and Trypan blue viability assay against colorectal cancer cell lines (HCT116) and non-small cell lung cancer cell lines (H460). Human Epithelial Kidney cell lines (HEK) are used as normal cell lines for studying effect of drug on non-cancerous cells within human body. Evaluation of cytotoxic studies of synthesized compounds CHL(1-8) reveal that compound CHL1 [IC50=7.31 and 10.16 µM against HCT116 and H460 cell lines respectively, by PI assay] and CHL8 [IC50=12.52 and 6.83 against HCT116 and H460µM cell lines respectively] possess promising cytotoxic activity.