Structural insights of dipeptidyl peptidase-IV inhibitors through molecular dynamics-guided receptor-dependent 4D-QSAR studies.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are promising antidiabetic agents. Currently, several DPP-IV inhibitors have been approved for therapeutic use in diabetes mellitus. Receptor-dependent 4D-QSAR is comparatively a new approach which uses molecular dynamics simulations to generate conformational ensemble profiles of compounds representing a dynamic state of compounds at a target's binding site. This work describes a receptor-dependent 4D-QSAR study on triazolopiperazine derivatives. QSARINS multiple linear regression method was adopted to generate 4D-QSAR models. A model with 9 variables was found to have better predictive accuracy with [Formula: see text], [Formula: see text] (leave-one-out) = 0.592 and [Formula: see text] predicted = 0.597. The location of these 9 variables at the binding site of DPP-IV revealed the importance of the residues Val711, Tyr662, Tyr666, Val202, Asp200 and Thr199 in making critical interactions with DPP-IV inhibitors. The study of these critical interactions revealed the structural features required in DPP-IV inhibitors. Thus, in this study the importance of a halogen substituent on a phenyl ring, the extent of substitution on the triazolopiperazine ring, the presence of an ionizable amino group and the presence of a hydrophobic substituent that can bind deeper in binding pocket of DPP-IV were revealed.

Kinetics of degradation of carbendazim by B. subtilis strains: possibility of in situ detoxification.

Food safety is a global concern due to the increased use of pesticides in agriculture. In grapes, carbendazim is one of the frequently detected fungicides. However, it is amenable to biodegradation. In this study, we aimed to assess the degradation of carbendazim by four Bacillus subtilis strains, which had earlier shown potential for biocontrol of grape diseases. In liquid medium, each of the four strains, namely, DR-39, CS-126, TL-171, and TS-204, could utilize carbendazim as the sole carbon source. The half-life was minimized from 8.4 days in the uninoculated spiked control to 4.0-6.2 days by the four strains. In Thompson Seedless sprayed with carbendazim at 1.0 g L(-1), the residue on grape berries in control was 0.44 mg kg(-1) after 25 days of application, whereas in grapes treated with the four B. subtilis strains, the residues had decreased to 0.02 mg kg(-1). The degradation kinetics showed low half-lives of 3.1 to 5.2 days in treated grapes as compared to 8.8 days in control. In inoculated soils, the half-lives were 5.9 to 7.6 days in autoclaved and 6.5 to 7.2 days in nonautoclaved soils as compared to 8.2 and 8.0 days in respective controls. The growth dynamics of these strains in all the three matrices was not affected by presence of carbendazim. Bacillus strains TS-204 and TL-171 showed higher degradation rate than the other two strains in all the three matrices and show promise for in situ biodegradation of carbendazim.

Letter to the editor: Characterization of a Grapevine leafroll-associated virus 3 from India showing incongruence in its phylogeny.

Survey conducted during 2010-2011 in the vineyards of Nashik and Pune regions of India revealed the association of an Ampelovirus antigenically related to Grapevine leafroll-associated virus 3 (GLRaV-3) with seven cultivars of grapevine. Upon sequencing of the coat protein (CP) and partial heat shock protein 70 homologue (HSP70h) genes of GLRaV-3 present in the cultivar Cabernet Souvignon showed distinct grouping behaviour. It clustered in group 2 and group 1 on the basis of CP and HSP70h sequences, respectively. Incongruent clustering pattern observed on the basis of two genomic regions suggest that GLRaV-3 is a distinct isolate from India.

Patent landscape for discovery of promising acyltransferase DGAT and MGAT inhibitors.

INTRODUCTION: DGAT and MGAT enzymes play an important role in triacylglycerol (TGA) biosynthesis. Overexpression of these enzymes may lead to accumulation of TGA in adipose tissues causing development of diseases such as obesity and diabetes. High triglyceride levels increase risk factors for atherosclerosis, and increase the risk of heart attack, stroke and other heart diseases. DGAT and MGAT inhibitors are used for the treatment of such metabolic diseases. A number of DGAT and MGAT inhibitors entered into clinical and preclinical stages. However, some adverse effects are associated with them. Thus there is need to develop new, potent and safe DGAT and MGAT inhibitors. AREA COVERED: In this review, the authors carefully searched patent literature and reviewed recent advances since the year 2014. Diverse chemical classes reported in the patents belonging to the category DGAT and MGAT inhibitors have been highlighted. EXPERT OPINION: DGAT and MGAT inhibitors are now gaining significant importance in the treatment of metabolic diseases. Fused heterocycles with a combination of aromatic and aliphatic hydrophobic substituents could offer more potent DGAT and MGAT inhibitors. Previously reported chemical scaffolds and their DGAT and MGAT inhibitory activity could be employed as an input for some in silico studies to discover novel, potent and safe DGAT and MGAT inhibitors.

3D-QSAR with R: A new 3D-QSAR methodology applied to a set of DGAT1 inhibitors [corrected].

The rapid advances in computational methods for the drug design have resulted in the accurate predictions of biological activities of ligands with or without the availability of enzyme structures. 3D-QSAR is one of the computational methods used for such purpose. Currently, freely available 3D-QSAR methods suffer the limitations like complex methodologies, difficulty in the analysis of results, applying the statistical methods and validations of models built. Present work describes simple and novel 3D-QSAR methodology, which uses bash scripts LQTA_R_LJ, LQTA_R_QQ and LQTA_R_HB using freely available R statistical program. These scripts then generate Leenard-Jones, Coulomb and Hydrogen bond descriptors. These descriptors provide the steric 3D property, electrostatic property and hydrogen bond formation capacity respectively. These scripts have been tested for the set of DGAT1 inhibitors and results showed that the 3D-QSAR models built have better predictive abilities in terms of R2 0.735, Q2loo 0.635 and R2ext 0.715. The 3D-QSAR model suggested that the substitutions of the alkyl group at the oxadiazolyl ring at the 6th position of the pyrrolo-pyridazine ring is undesirable, on the contrary, substituted phenyl ring at 7th position is responsible for the improved DGAT1 inhibitory activity. The analysis also suggested that 6th position could be substituted with the oxadiazolyl ring or analogous heterocyclic rings, where the 3rd position of such heterocyclic rings substituted with rigid hydrophobic substitute can improve DGAT1 activity.

Enhanced Dissipation of Triazole and Multiclass Pesticide Residues on Grapes after Foliar Application of Grapevine-Associated Bacillus Species.

Disease management in vineyards with fungicides sometimes results in undesirable residue accumulations in grapes at harvest. Bioaugmentation of the grape fructosphere can be a useful approach for enhancing the degradation rate and reducing the residues to safe levels. This paper reports the in vitro and in vivo biodegradation of three triazole fungicides commonly used in Indian vineyards, by Bacillus strains, namely, DR-39, CS-126, TL-171, and TS-204, which were earlier found to enhance the dissipation rate of profenophos and carbendazim. The strains utilized the triazoles as carbon source and enhanced their in vitro rate of degradation. Myclobutanil, tetraconazole, and flusilazole were applied in separate vineyard plots at field doses of 0.40 g L(-1), 0.75 mL L(-1), and 0.125 mL L(-1), respectively. Residue analysis of field samples from the treated fields reflected 87.38 and >99% degradations of myclobutanil and tetraconazole, respectively, by the strain DR-39, and 90.82% degradation of flusilazole by the strain CS-126 after 15-20 days of treatment. In the respective controls, the corresponding percent degradations were 72.07, 58.88, and 54.28, respectively. These Bacillus strains could also simultaneously degrade the residues of profenofos, carbendazim, and tetraconazole on the grape berries and can be useful in multiclass pesticide residue biodegradation.

Biodegradation of profenofos by Bacillus subtilis isolated from grapevines (Vitis vinifera).

The biodegradation of profenofos, an organophosphorus insecticide, by four Bacillus subtilis strains, namely, DR-39, CS-126, TL-171, and TS-204, isolated from grapevines or grape rhizosphere was studied in liquid culture, on grape berries, and in vineyard soil. Each of the four B. subtilis strains enhanced the degradation of profenofos in all three matrices. Degradation rate constants were best obtained by first + first-order kinetics module. In nutrient broth spiked with 5 µg/mL profenofos, inoculation with B. subtilis strains DR-39, CS-126, TL-171, and TS-204 reduced the half-life (DT50) of profenofos to 4.03, 3.57, 2.87, and 2.53 days, respectively, from the DT50 = 12.90 days observed in the uninoculated control. In Thompson Seedless grapes sprayed with profenofos at a field dose of 1250 mL ai/ha, the DT50 values were 1.07, 1.00, 2.13, and 2.20 days in grapes inoculated with B. subtilis strains DR-39, CS-126, TL-171, and TS-204, respectively, as compared to 2.20 days in uninoculated grapes. These four B. subtilis strains also enhanced the degradation of profenofos in autoclaved soil (DT50 = 5.93, 7.47, 6.00, and 4.37 days) and in nonautoclaved soil (DT50 = 0.87, 2.00, 2.07, and 2.43 days) amended with 5 µg/g profenofos from the half-lives of 17.37 and 14.37 days in respective uninoculated soils. Growth dynamic studies indicated that all four B. subtilis strains were able to establish and proliferate on berries and soil equally well in the presence or absence of profenofos. Degradation product 4-bromo-2-chlorophenol was identified by GC-MS. Strain DR-39 was most effective in the natural environments of grape and soil.