Concentration-dependent mode of binding of drug oxatomide with DNA: multi-spectroscopic, voltammetric and metadynamics simulation analysis.

The interaction between antihistaminic drug oxatomide (OXT) and calf-thymus DNA (CT-DNA) has been investigated in a physiological buffer (pH 7.4) using UV-Vis, fluorescence, 1H NMR and circular dichroism spectral techniques coupled with viscosity measurements, KI quenching, voltammetry and in silico molecular modeling studies. OXT binds with CT-DNA in a concentration-dependent manner. At a lower [Drug]/[CT-DNA] molar ratio (0.6-0.1), OXT intercalates into the base pairs of CT-DNA, while at a higher [Drug]/[CT-DNA] molar ratio (13-6), the drug binds in the minor grooves of CT-DNA. The binding constants for the interaction are found to be in the order of 103-105 M-1, and the groove binding mode of interaction exhibits a slightly higher binding constant than that of intercalative mode. Thermodynamic analysis of binding constants at three different temperatures suggests that both these modes of binding are mainly driven by hydrophobic interactions (ΔHo > 0 and ΔSo > 0). Voltammetric investigations indicate that the electro-reduction of OXT is an adsorption controlled process and shifts in reduction peak potentials reiterate the concentration-dependent mode of binding of the drug with CT-DNA. The free energy landscape obtained at the all-atom level, using metadynamics simulation studies, revealed two major binding forces: partial intercalation and minor groove binding, which corroborate well with the experimental results.Communicated by Ramaswamy H. Sarma.

Highly selective turn-on fluorescent probe for detection of cyanide in water and food materials.

A naphthoquinone-imine based fluorescent probe (R) has been synthesized and characterized by NMR and mass spectral techniques. The receptor shows high selectivity towards cyanide in water in the presence of other competitive anions with an instantaneous colour change from non-emissive to green under UV light. The turn-on fluorescence is due to deprotonation of three hydroxyl groups by cyanide ions as evidenced from 1H NMR titration experiment. The LOD of cyanide by R in water is 0.6 µM, which is much lower than the permissible limit of cyanide in drinking water according to the WHO.

Application of Various Statistical Models to Explore Gene-Gene Interactions in Folate, Xenobiotic, Toll-Like Receptor and STAT4 Pathways that Modulate Susceptibility to Systemic Lupus Erythematosus.

INTRODUCTION: In view of our previous studies showing an independent association of genetic polymorphisms in folate, xenobiotic, and toll-like receptor (TLR) pathways with the risk for systemic lupus erythematosus (SLE), we have developed three statistical models to delineate complex gene-gene interactions between folate, xenobiotic, TLR, and signal transducer and activator of transcription 4 (STAT4) signaling pathways in association with the molecular pathophysiology of SLE. METHODS: We developed additive, multifactor dimensionality reduction (MDR), and artificial neural network (ANN) models. RESULTS: The additive model, although the simplest, suggested a moderate predictability of 30 polymorphisms of these four pathways (area under the curve [AUC] 0.66). MDR analysis revealed significant gene-gene interactions among glutathione-S-transferase (GST)T1 and STAT4 (rs3821236 and rs7574865) polymorphisms, which account for moderate predictability of SLE. The MDR model for specific auto-antibodies revealed the importance of gene-gene interactions among cytochrome P450, family1, subfamily A, polypeptide 1 (CYP1A1) m1, catechol-O-methyltransferase (COMT) H108L, solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A, estrogen receptor 1 (ESR1), TLR5, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), thymidylate synthase (TYMS). and STAT4 polymorphisms. The ANN model for disease prediction showed reasonably good predictability of SLE risk with 30 polymorphisms (AUC 0.76). These polymorphisms contribute towards the production of SSB and anti-dsDNA antibodies to the extent of 48 and 40%, respectively, while their contribution for the production of antiRNP, SSA, and anti-cardiolipin antibodies varies between 20 and 30%. CONCLUSION: The current study highlighted the importance of genetic polymorphisms in folate, xenobiotic, TLR, and STAT4 signaling pathways as moderate predictors of SLE risk and delineates the molecular pathophysiology associated with these single nucleotide polymorphisms (SNPs) by demonstrating their association with specific auto-antibody production.