A comprehensive in silico exploration of pharmacological properties, bioactivities and COX-2 inhibitory potential of eleutheroside B from Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim., popularly known as 'Siberian ginseng', is an important medicinal plant. Pharmacologically active compounds of this plant are called eleutherosides and among them, eleutheroside B is the most prevalent. The E. senticosus has been reported to have many medicinal properties however; very few studies are reported to understand the medicinal properties of eleutheroside B. Consequently, in the present study various computational tools have been used to predict the drug-likeness, bioactivities, and pharmacokinetic properties of eleutheroside B. Besides, the inhibitory potential of eleutheroside B has been investigated against cyclooxygenase 2 (COX-2) enzyme. This study suggests that eleutheroside B is a drug-like compound with bioactivity score (-0.08 to 0.38), having satisfactory pharmacokinetic values. Metabolism and toxicities were further studied using FAME3, GLORY, pred-hERG and Endocrine Disruptome tools. No severe toxicities (Ames, hepatotoxicity, cardiotoxicity, skin sensitization) were predicted. Rat acute toxicity, ecotoxicity and cell line cytotoxicity were evaluated based on GUSAR and CLC-pred. The compound has been predicted as non-toxic (class 5), non-hERG inhibitor and less likely to cause adverse drug interactions. Molecular docking against COX-2 enzyme revealed strong hydrogen bonds (SER530, TYR355, LEU352, SER353, VAL349, TYR385, MET522) and hydrophobic interaction (LEU352) with eleutheroside B. The docking score (-6.97 kcal/mol) suggested that this molecule can be utilized as an anti-inflammatory agent as well as a potential anticancer drug in the future. Hence, this is a comprehensive integrated in silico approach to establish the anti-inflammatory mechanism of eleutheroside B in the background of its potential in future drug development.Communicated by Ramaswamy H. Sarma.

Insights into the antibiotic resistance and inhibition mechanism of aminoglycoside phosphotransferase from Bacillus cereus: In silico and in vitro perspective.

Because of the lack of structural studies on aminoglycoside phosphotransferase (APH) from prevalent volatile human pathogen Bacillus cereus, aminoglycoside resistance therapeutics research remains elusive. Hence, in this computational study, we have performed homology modeling, molecular docking, molecular dynamics (MD), and principal component analysis studies on APH from B. cereus. The structure of APH was predicted by homology modeling using MODELLER 9v12 and validated for its stereochemical qualities. Sequence analysis study of the template (Protein Data Bank ID: 3TDW) and APH from B. cereus sensu lato group showed exact matching of active-site residues. The mechanism of substrate and inhibitor binding to APH was studied using molecular docking, which identified GTP as the more preferred substrate, whereas ZINC71575479 as the most effective inhibitor. The active-site residues, ARG41, TYR90, ASP195, and ASP215 at nucleotide triphosphate-binding cavity of APH were found to be involved in binding with substrate and inhibitor. Molecular dynamics simulation study of APH in apo form and bound form confirmed the stability and effective binding of GTP and ZINC71575479 in a dynamic state. Molecular mechanics Poisson-Boltzmann surface area calculations revealed energetic contributions of active-site residues of APH in binding with GTP and ZINC71575479. The principal component analysis revealed the internal global motion of APH in apo and complex form. Furthermore, experimental studies on APH from B. cereus ATCC 10876 validated the in silico findings for its inhibition. Thus, this study provides more information on structure-function relationships of APH from B. cereus and open avenues for designing effective strategies to overcome antibiotic resistance.

Exploring mode of phosphoramidon and Aß peptide binding to hECE-1 by molecular dynamics and docking studies.

Human Endothelin converting enzyme (hECE-1) has been widely known for its involvement in hydrolyzing Aß peptides at multiple sites. In the present study we have performed molecular dynamics (MD) simulation of crystal structure complex of hECE-1 and its inhibitor phosphoramidon with Zn ion to understand the dynamic behavior of active site residues. Root Mean Square Deviation (RMSD) results revealed that enzyme hECE-1 structure was highly stable throughout the simulation period. The L-leucyl-L-tryptophan moiety and N-phosphoryl moiety of phosphoramidon was found in the S1 and S2 pockets of hECE-1 respectively. The inhibitor was stabilized by hydrogen bonding interactions with residues Arg 145, Asn 566, Pro 731 and His 732 of hECE-1. Based on this information molecular docking of hECE- 1 crystal structure with three different structures of Aß peptides has been performed. Zinc ion interacts with His 607(NE2), His 611(NE2), Glu 667 (OE1, OE2) and backbone oxygen atom of Phe 19 showing catalytic coordination between Aß peptide and hECE-1. The unusual orientation of Aß peptide residues affects hydrophobic interactions and hydrogen bonding network between hECE-1 and Aß peptide. The molecular basis of amyloid beta peptide cleavage by hECE-1 could aid in designing enzyme based therapies to control Aß peptide concentration in Alzheimer's patient.