Design of EGFR kinase inhibitors: a ligand-based approach and its confirmation with structure-based studies

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 100 anilinoquinazolines, inhibiting epidermal growth factor receptor (EGFR) kinase. The studies included molecular field analysis (MFA) and receptor surface analysis (RSA). The cross-validated r2 (r2cv) values are 0.81 and 0.79 for MFA and RSA, respectively. The predictive ability of these models was validated by 28 test set molecules. The results of the best QSAR model were further compared with structure-based investigations using docking studies with the crystal structure of EGFR kinase domain. The results helped to understand the nature of substituents at the 6- and 7-positions, thereby providing new guidelines for the design of novel inhibitors.     

Genotype Variability in Photosynthetic Characteristics in Finger Millet

High variability in leaf gas exchange and related traits were found in 30 genotypes of field grown finger millet. The variability in carbon exchange rate per unit leaf area (P _N) can be partly attributed to the differences in the stomatal conductance (g_s) and area leaf mass (ALM). The P _N was positively correlated with total dry matter (TDM). However, no relationship between P _N and seed yield was found. The leaf area showed a positive and significant correlation with total biomass. None of the other gas-exchange traits had significant relationship either with TDM or with seed yield. The ALM showed a strong positive association with P _N. However, it was not correlated with either total biomass or seed yield. As a result, the use of ALM as surrogate for P _N for identifying high biomass producing genotypes only had a limited value. Hence selection for high P _N would result in higher biomass producing types.     

14CO2 Assimilation and 14C-photosynthate Translocation in Different Leaves of Sunflower

Chlorophyll and nitrogen contents were highest in leaves of middle position, similarly as photosynthetic efficiency represented by ¹⁴C fixation (maxima in leaf 5 from the top). All the leaves lost ¹⁴C after 2 weeks of ¹⁴CO₂ exposure. However, the reduction in radioactivity was less in young upper leaves than in the mature lower leaves. Leaves exported ¹⁴C-photosynthates to stem both above and below the exposed leaf. Very little radioactivity was recovered from the seeds of plants in which only first or second leaves were exposed to ¹⁴CO₂ implying thereby that the carbon contribution of first two leaves to seed filling was negligible. The contribution of leaves to seed filling increased with the leaf position up to the sixth leaf from the top and after the seventh leaf their contribution to seed filling declined gradually.     

Pan-genome dynamics of Pseudomonas gene complements enriched across hexachlorocyclohexane dumpsite

Background

Phylogenetic heterogeneity across Pseudomonas genus is complemented by its diverse genome architecture enriched by accessory genetic elements (plasmids, transposons, and integrons) conferring resistance across this genus. Here, we sequenced a stress tolerant genotype i.e. Pseudomonas sp. strain RL isolated from a hexachlorocyclohexane (HCH) contaminated pond (45 mg of total HCH g⁻¹ sediment) and further compared its gene repertoire with 17 reference ecotypes belonging to P. stutzeri, P. mendocina, P. aeruginosa, P. psychrotolerans and P. denitrificans, representing metabolically diverse ecosystems (i.e. marine, clinical, and soil/sludge). Metagenomic data from HCH contaminated pond sediment and similar HCH contaminated sites were further used to analyze the pan-genome dynamics of Pseudomonas genotypes enriched across increasing HCH gradient.

Results

Although strain RL demonstrated clear species demarcation (ANI ≤ 80.03%) from the rest of its phylogenetic relatives, it was found to be closest to P. stutzeri clade which was further complemented functionally. Comparative functional analysis elucidated strain specific enrichment of metabolic pathways like α-linoleic acid degradation and carbazole degradation in Pseudomonas sp. strain RL and P. stutzeri XLDN-R, respectively. Composition based methods (%codon bias and %G + C difference) further highlighted the significance of horizontal gene transfer (HGT) in evolution of nitrogen metabolism, two-component system (TCS) and methionine metabolism across the Pseudomonas genomes used in this study. An intact mobile class-I integron (3,552 bp) with a captured gene cassette encoding for dihydrofolate reductase (dhfra1) was detected in strain RL, distinctly demarcated from other integron harboring species (i.e. P. aeruginosa, P. stutzeri, and P. putida). Mobility of this integron was confirmed by its association with Tnp21-like transposon (95% identity) suggesting stress specific mobilization across HCH contaminated sites. Metagenomics data from pond sediment and recently surveyed HCH adulterated soils revealed the in situ enrichment of integron associated transposase gene (TnpA6100) across increasing HCH contamination (0.7 to 450 mg HCH g⁻¹ of soil).

Conclusions

Unlocking the potential of comparative genomics supplemented with metagenomics, we have attempted to resolve the environment and strain specific demarcations across 18 Pseudomonas gene complements. Pan-genome analyses of these strains indicate at astoundingly diverse metabolic strategies and provide genetic basis for the cosmopolitan existence of this taxon.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1488-2) contains supplementary material, which is available to authorized users.     

Interrelationship between Leaf Gas-Exchange Characteristics,Area Leaf Mass,and Yield in Soybean (Glycine max L. Merr) Genotypes

Variability in leaf gas-exchange traits in thirteen soybean (Glycine max L. Merr) genotypes was assessed in a field experiment conducted at high altitude (1 950 m). Leaf net photosynthetic rate (P ^N) exhibited a high degree of variability at all the growth stages studied. P _N and other gas-exchange parameters exhibited a seasonal pattern that was similar for all the genotypes. P _N rate was highest at seed filling stage. P _N was positively and significantly associated with aboveground dry matter and seed yield. The area leaf mass (ALM) exhibited a strong positive association with leaf P _N, aboveground dry matter, and seed yield. The positive association between ALM, P _N, and seed yield suggests that this simple and easy to measure character can be used in breeding programmes as a surrogate for higher photosynthetic efficiency and eventually higher yield.     

Characterization of backcross introgression lines derived from <Emphasis Type="Italic">Oryza nivara</Emphasis> accessions for photosynthesis and yield

Improvement of photosynthetic traits is a promising strategy to break the yield potential barrier of major food crops. Leaf photosynthetic traits were evaluated in a set of high yielding Oryza sativa, cv. Swarna?×?Oryza nivara backcross introgression lines (BILs) along with recurrent parent Swarna, both in wet (Kharif) and dry (Rabi) seasons in normal irrigated field conditions. Net photosynthesis (P_N) ranged from 15.37 to 23.25 µmol (CO₂) m^?2 s^?1 in the BILs. Significant difference in P_N was observed across the seasons and genotypes. Six BILs showed high photosynthesis compared with recurrent parent in both seasons. Chlorophyll content showed minimum variation across the seasons for any specific BIL but significant variation was observed among BILs. Significant positive association between photosynthetic traits and yield traits was observed, but this association was not consistent across seasons mainly due to contrasting weather parameters in both seasons. BILs 166s and 248s with high and consistent photosynthetic rate exhibited stable high yield levels in both the seasons compared to the recurrent parent Swarna. There is scope to exploit photosynthetic efficiency of wild and weedy rice to identify genes for improvement of photosynthetic rate in cultivars.     

3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods

Three dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on deoxythymidine monophosphate (dTMP) derivatives inhibiting thymidine monophosphate kinase (TMPK) in Mycobacterium tuberculosis. Molecular field analysis (MFA) models with three different alignment techniques, namely, least squares, pharmacophore based and receptor based methods were developed. Receptor based MFA model showed better results when compared with least squares and pharmacophore based models. The results help us to understand the nature of substituents required for activity and thereby provide guidelines to design novel and potent inhibitors as antitubercular agents.     

Strong and weak hydrogen bonds in drug-DNA complexes: A statistical analysis

A statistical analysis of strong and weak hydrogen bonds in the minor groove of DNA was carried out for a set of 70 drug-DNA complexes. The terms ‘strong’ and ‘weak’ pertain to the inherent strengths and weakness of the donor and acceptor fragments rather than to any energy considerations. The dataset was extracted from the protein data bank (PDB). The analysis was performed with an in-house software, hydrogen bond analysis tool (HBAT). In addition to strong hydrogen bonds such as O—H⋯O and N—H⋯O, the ubiquitous presence of weak hydrogen bonds such as C—H⋯O is implicated in molecular recognition. On an average, there are 1.4 weak hydrogen bonds for every strong hydrogen bond. For both categories of interaction, the N(3) of purine and the O(2) of pyrimidine are favoured acceptors. Donor multifurcation is common with the donors generally present in the drug molecules, and shared by hydrogen bond acceptors in the minor groove. Bifurcation and trifurcation are most commonly observed. The metrics for strong hydrogen bonds are consistent with established trends. The geometries are variable for weak hydrogen bonds. A database of recognition geometries for 26 literature amidinium-based inhibitors of Human African Trypanosomes (HAT) was generated with a docking study using seven inhibitors which occur in published crystal structures included in the list of 70 complexes mentioned above, and 19 inhibitors for which the drug-DNA complex crystal structures are unknown. The virtual geometries so generated correlate well with published activities for these 26 inhibitors, justifying our assumption that strong and weak hydrogen bonds are optimized in the active site.