Total Synthesis and Biological Profiling of Putative (±)-Marinoaziridine B and (±)-N-Methyl Marinoaziridine A.

The total synthesis of two new marine natural products, (±)-marinoaziridine B 7 and (±)-N-methyl marinoaziridine A 8, was accomplished. The (±)-marinoaziridine 7 was prepared in a six-step linear sequence with a 2% overall yield. The key steps in our strategy were the preparation of the chiral epoxide (±)-5 using the Johnson Corey Chaykovsky reaction, followed by the ring-opening reaction and the Staudinger reaction. The N,N-dimethylation of compound (±)-7 gives (±)-N-methyl marinoaziridine A 8. The NMR spectra of synthetized (±)-marinoaziridine B 7 and isolated natural product did not match. The compounds are biologically characterized using relevant in silico, in vitro and in vivo methods. In silico ADMET and bioactivity profiling predicted toxic and neuromodulatory effects. In vitro screening by MTT assay on three cell lines (MCF-7, H-460, HEK293T) showed that both compounds exhibited moderate to strong antiproliferative and cytotoxic effects. Antimicrobial tests on bacterial cultures of Escherichia coli and Staphylococcus aureus demonstrated the dose-dependent inhibition of the growth of both bacteria. In vivo toxicological tests were performed on zebrafish Danio rerio and showed a significant reduction of zebrafish mortality due to N-methylation in (±)-8.

Effect of temperature on hepatitis a virus and exploration of binding mode mechanism of phytochemicals from tinospora cordifolia: an insight into molecular docking, MM/GBSA, and molecular dynamics simulation study.

The hepatitis A virus (HAV), which causes hepatitis A, is a contagious liver ailment. The infections are not specifically treated by any medications. Therefore, the development of less harmful, more effective and cost-effective antiviral agents are necessary. The present work highlighted the in-silico activity of phytocompounds from tinospora cordifolia against HAV. The binding interaction of HAV with the phytocompounds was analyzed through molecular docking. Molecular docking revealed that chasmanthin, malabarolide, menispermacide, tinosporaside, and tinosporinone compounds bind with HAV more efficiently than other compounds. Further evaluation using 100 ns molecular dynamics simulation, MM/GBSA and free energy landscape indicated that all phytocompounds studied here were found to be most promising drug candidate against hepatitis A virus. Our computational study will encourage promoting in further investigation for in vitro and in vivo clinical trials.Communicated by Ramaswamy H. Sarma.

Computational normal mode analysis accurately replicates the activity and specificity profiles of CRISPR-Cas9 and high-fidelity variants.

The CRISPR-Cas system has transformed the field of gene-editing and created opportunities for novel genome engineering therapeutics. The field has significantly progressed, and recently, CRISPR-Cas9 was utilized in clinical trials to target disease-causing mutations. Existing tools aim to predict the on-target efficacy and potential genome-wide off-targets by scoring a particular gRNA according to an array of gRNA design principles or machine learning algorithms based on empirical results of large numbers of gRNAs. However, such tools are unable to predict the editing outcome by variant Cas enzymes and can only assess potential off-targets related to reference genomes. Here, we employ normal mode analysis (NMA) to investigate the structure of the Cas9 protein complexed with its gRNA and target DNA and explore the function of the protein. Our results demonstrate the feasibility and validity of NMA to predict the activity and specificity of SpyCas9 in the presence of mismatches by comparison to empirical data. Furthermore, despite the absence of their exact structures, this method accurately predicts the enzymatic activity of known high-fidelity engineered Cas9 variants.

Prunus amygdalus extract exert antidiabetic effect via inhibition of DPP-IV: in-silico and in-vivo approaches.

Prunus amygdalus (PA) is a popular invasive seed utilized in the management of diabetes in Jammu and Kashmir, India. The objective of the current study was to scrutinize the antidiabetic effect of Prunus amygdalus (PA) against Streptozotocin (STZ) induced diabetic rats and explore the possible mechanism of action at cellular and sub-cellular levels. Box Benkan Design (BBD) was performed to determine the effect of PA powder to methanol, extraction time and extraction temperature on DPPH and ABTS free radical scavenging activity of decoction. In-silico study was performed on GLUT1 (5EQG) and dipeptidyl peptidase IV (DPPIV) (2G63) protein. Type II diabetes mellitus was initiated by single intra-peritoneal injection of STZ. The Blood Glucose Level (BGL) and body weight were estimated at regular interval of time. The different biochemical parameters such as hepatic, antioxidant, and lipid parameters were estimated. At end of the study, pancreas was used for histopathological observation. The variation in DPPH antiradical scavenging activity 40.0-90.0% and ABTS antiradical scavenging activity 34-82%, were estimated respectively. STZ induced DM rats showed increased BGL at end of the experimental study. PA treatment significantly (p < 0.001) down-regulated the BGL level. PA significantly (p < 0.001) altered the biochemical, hepatic and antioxidant parameters in a dose-dependent manner. Histopathological examination demonstrated the constructive mass of ß-cells in pancreas. Overall, the current study indicates that the PA treatment down-regulated the hyperglycemic, oxidative stress and hyperlipidaemia in diabetic rats, due to inhibition of enzymes or amelioration of oxidative stress. [Formula: see text] Communicated by Ramaswamy H. Sarma.