Analogue-based approaches in anti-cancer compound modelling: the relevance of QSAR models

Background: QSAR is among the most extensively used computational methodology for analogue-based design. The application of various descriptor classes like quantum chemical, molecular mechanics, conceptual density functional theory (DFT)- and docking-based descriptors for predicting anti-cancer activity is well known. Although in vitro assay for anti-cancer activity is available against many different cell lines, most of the computational studies are carried out targeting insufficient number of cell lines. Hence, statistically robust and extensive QSAR studies against 29 different cancer cell lines and its comparative account, has been carried out. Results: The predictive models were built for 266 compounds with experimental data against 29 different cancer cell lines, employing independent and least number of descriptors. Robust statistical analysis shows a high correlation, cross-validation coefficient values, and provides a range of QSAR equations. Comparative performance of each class of descriptors was carried out and the effect of number of descriptors (1-10) on statistical parameters was tested. Charge-based descriptors were found in 20 out of 39 models (approx. 50%), valency-based descriptor in 14 (approx. 36%) and bond order-based descriptor in 11 (approx. 28%) in comparison to other descriptors. The use of conceptual DFT descriptors does not improve the statistical quality of the models in most cases. Conclusion: Analysis is done with various models where the number of descriptors is increased from 1 to 10; it is interesting to note that in most cases 3 descriptor-based models are adequate. The study reveals that quantum chemical descriptors are the most important class of descriptors in modelling these series of compounds followed by electrostatic, constitutional, geometrical, topological and conceptual DFT descriptors. Cell lines in nasopharyngeal (2) cancer average R2 = 0.90 followed by cell lines in melanoma cancer (4) with average R2 = 0.81 gave the best statistical values

Determinants of Intravascular Resistance in Indian Diabetic Nephropathy Patients: A Hospital-Based Study

Aims and Objectives. Metabolic dysregulation has failed to explain clinical variability of patients with diabetic nephropathy and hence a renewed interest emerged in haemodynamic factors as determinant of progression and development of diabetic nephropathy. We therefore studied for various factors which can correlate with raised renal vascular resistance in diabetic nephropathy. Material and Methods. Renal vascular resistance was measured in patients with established and incipient diabetic nephropathy and compared with controls using noninvasive color Doppler examinations of intrarenal vasculature. Results. Renal vascular resistance correlated with age, duration of disease, GFR, serum creatinine, and stage of retinopathy. Renal vascular resistance was significantly reduced in patients on treatment with RAAS inhibitors and insulin, than those on OHA and antihypertensives other than RAAS inhibitors. Conclusion. The study implies that renal vascular resistance may help identify diabetics at high risk of developing nephropathy, and these set of patients could be candidates for RAAS inhibition and early insulin therapy even in patients without albuminuria

Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

<p>Abstract</p> <p>Background</p> <p>The World Health Organization has urged all member states to deploy artemisinin-based combination therapy and progressively withdraw oral artemisinin monotherapies from the market due to their high recrudescence rates and to reduce the risk of drug resistance. Prescription practices by physicians and the availability of oral artemisinin monotherapies with pharmacists directly affect the pattern of their use. Thus, treatment practices for malaria, with special reference to artemisinin monotherapy prescription, in selected states of India were evaluated.</p> <p>Methods</p> <p>Structured, tested questionnaires were used to conduct convenience surveys of physicians and pharmacists in eleven purposively selected districts across six states in 2008. In addition, exit interviews of patients with a diagnosis of uncomplicated malaria or a prescription for an anti-malarial drug were also performed. Logistic regression was used to determine patient clinical care, and institutional factors associated with artemisinin monotherapy prescription.</p> <p>Results</p> <p>Five hundred and eleven physicians from 196 health facilities, 530 pharmacists, and 1, 832 patients were interviewed. Artemisinin monotherapy was available in 72.6% of pharmacies and was prescribed by physicians for uncomplicated malaria in all study states. Exit interviews among patients confirmed the high rate of use of artemisinin monotherapy with 14.8% receiving such a prescription. Case management, i.e. method of diagnosis and overall treatment, varied by state and public or private sector. Treatment in the private sector (OR 8.0, 95%CI: 3.8, 17) was the strongest predictor of artemisinin monotherapy prescription when accounting for other factors. Use of the combination therapy recommended by the national drug policy, artesunate + sulphadoxine-pyrimethamine, was minimal (4.9%), with the exception of one state.</p> <p>Conclusions</p> <p>Artemisinin monotherapy use was widespread across India in 2008. The accessible sale of oral artemisinin monotherapy in retail market and an inadequate supply of recommended drugs in the public sector health facilities promoted its prescription. This study resulted in notifications to all state drug controllers in India to withdraw the oral artemisinin formulations from the market. In 2010, artesunate + sulphadoxine-pyrimethamine became the universal first-line treatment for confirmed <it>Plasmodium falciparum </it>malaria and was deployed at full scale.</p

Aromatic Rice of India: It’s Types and Breeding Strategies

The coalescence of organoleptic traits viz., pleasant aroma, cooked rice texture, and taste make aromatic rice unique and distinguished from non-aromatic rice. Aromatic rice is cultivated in every rice growing country; with each country has its own indigenous collection. International trade of rice is dominated by Indica (long grained), Japonica (short grained), aromatic rice (Basmati and Jasmine) and glutinous rice; amidst which, Basmati types from India and Pakistan; and Jasmine types from Thailand have phenomenal demand. In India all types of aromatic rice are cultivated based on Kernel length; short, medium, long and very long grained. Basmati varieties own the major market, while other types of aromatic rice besides Basmati are popular in local market only. The country inherits rich diversity of aromatic rice germplasm; with more than 300 different types, each of the rice growing states of India has its own locally popular aromatic rice varieties. India a country where two third of its population consume rice as part of their daily food; aromatic rice always remain their favorite. Basmati, by virtue of its excellent qualities it dominates both national and international market. Every year, Basmati ranks first in respect of foreign exchange earned from the export of agricultural products from India (APEDA). The phenomenal demand and export figures have augmented Basmati Breeding program. However, only few aromatic varieties are cultivated depending on their demand, and their breeding program is also limited. In India, Basmati has over-shadowed other types of aromatic rice in market and in plant breeding programs too. Breeding for Basmati varieties is undertaken by prime agricultural institutions of India. The country regulates quality standards and development of Basmati varieties with the help of Export of Basmati Rice (Quality Control and Inspection) Rules 2003; Agricultural and Processed Food Products Export Development Authority (APEDA); and Basmati Export Development Foundation (BEDF). However, no such initiatives have been taken to promote the development of other aromatic rice varieties of India besides Basmati

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Not AvailablePhytic acid (PA) is an important antinutritional component in maize that affects the availability of major micro-nutrients like di- and multivalent mineral cations like iron (Fe) and zinc (Zn). The long-term consumption of maize as a staple food crop leads to micronutrient malnutrition especially iron and zinc deficiency in the human population. In addition, it also acts as a storehouse of a major part of mineral phosphorous (P), approximately 80% of the total P stored as phytate P is not available to monogastric animals like humans and poultry birds, and it gets excreted as such, leading to one of the major environmental pollution called eutrophication. Of the various low phytic acid (lpa) mutants, lpa2-2 generated through mutagenesis reduces PA by 30%. BML 6 and BML 45, the parents of the popular maize hybrid DHM 121 with high PA were selected to introgress lpa2-2 through marker-assisted backcross breeding (MABB). The percent recurrent parental genome (RPG) in the selected BC2F2 plants ranged from 88.68 to 91.04% and 90.09–91.51% in the genetic background of BML 6 and BML 45, respectively. Based on the highest percentage of RPG, best five BC2F2 plants, viz., #3190, #3283, #3230, #3263 and #3292 with RPG 88.68–91.04% in the genetic background of BML 6 and #3720, #3776, #3717, #3828 and #3832 with RPG 90.09–91.51% in the genetic background of BML 45 were advanced to BC2F3. The newly developed near-isogenic lines (NILs) possessed low phytate content (2.37 mg/g in BML 6 and 2.40 mg/g in BML 45) compared to 3.59 mg/g and 3.16 mg/g in recurrent parents BML 6 and BML 45, respectively thereby reducing the phytate by an average of 34 and 24 per cent, respectively. These newly developed progenies were similar to their recurrent parents for various morphological traits. These inbreds assume great significance in alleviating Fe and Zn deficiencies in worldwide.Not Availabl

Study of Structural, Magnetic and Electrical properties on Ho - substituted BiFeO3

The polycrystalline Bi1-xHoxFeO3 (x=0, 0.05, 0.1) compounds were synthesized by conventional solid-state route. Rietveld refinement reveals that all the compounds were stabilized in rhombohedral structure with R3c (IUCr No. 161) space group. A competing ferro and anti-ferro magnetic interaction was observed in Ho-substituted compounds. A change in the Fe-O-Fe bond-angle and Fe-O bond distance increase the Neel Transition temperature with increasing Ho concentration. The appearance of peak in imaginary part of impedance (Z") for each concentration and shifting of this peak with temperature towards higher frequency side indicated that the presence of electric relaxations. Correlated Barrier Hopping model (CBH) was employed to explain the frequency and temperature dependence of ac conductivity and the mechanism of transport in the material BFO and Ho substituted BFO. Density of states near Fermi level was calculated by using the ac conductivity data

Phenotypic Data from Inbred Parents Can Improve Genomic Prediction in Pearl Millet Hybrids

Pearl millet is a non-model grain and fodder crop adapted to extremely hot and dry environments globally. In India, a great deal of public and private sectors’ investment has focused on developing pearl millet single cross hybrids based on the cytoplasmic-genetic male sterility (CMS) system, while in Africa most pearl millet production relies on open pollinated varieties. Pearl millet lines were phenotyped for both the inbred parents and hybrids stage. Many breeding efforts focus on phenotypic selection of inbred parents to generate improved parental lines and hybrids. This study evaluated two genotyping techniques and four genomic selection schemes in pearl millet. Despite the fact that 6· more sequencing data were generated per sample for RAD-seq than for tGBS, tGBS yielded more than 2· as many informative SNPs (defined as those having MAF \u3e 0.05) than RAD-seq. A genomic prediction scheme utilizing only data from hybrids generated prediction accuracies (median) ranging from 0.73-0.74 (1000- grain weight), 0.87-0.89 (days to flowering time), 0.48-0.51 (grain yield) and 0.72-0.73 (plant height). For traits with little to no heterosis, hybrid only and hybrid/inbred prediction schemes performed almost equivalently. For traits with significant mid-parent heterosis, the direct inclusion of phenotypic data from inbred lines significantly (P \u3c 0.05) reduced prediction accuracy when all lines were analyzed together. However, when inbreds and hybrid trait values were both scored relative to the mean trait values for the respective populations, the inclusion of inbred phenotypic datasets moderately improved genomic predictions of the hybrid genomic estimated breeding values. Here we show that modern approaches to genotyping by sequencing can enable genomic selection in pearl millet. While historical pearl millet breeding records include a wealth of phenotypic data from inbred lines, we demonstrate that the naive incorporation of this data into a hybrid breeding program can reduce prediction accuracy, while controlling for the effects of heterosis per se allowed inbred genotype and trait data to improve the accuracy of genomic estimated breeding values for pearl millet hybrids

Viability of clathrate hydrates as CO<SUB>2</SUB> capturing agents: a theoretical study

Capture and sequestration of green house gas CO<SUB>2</SUB> is a major challenge for scientists and identifying right materials for this purpose is a task of outstanding importance. Through reliable computational studies, we have demonstrated that the clathrate cages (5<SUP>12</SUP>, 4<SUP>3</SUP>5<SUP>6</SUP>6<SUP>3</SUP>, 5<SUP>12</SUP>6<SUP>2</SUP>, 5<SUP>12</SUP>6<SUP>4</SUP>, and 5<SUP>12</SUP>6<SUP>8</SUP>) have a great potential to store CO<SUB>2</SUB>. All the considered clathrates and their CO<SUB>2</SUB> inclusion complexes are optimized at B3LYP/6-31G(d) level of theory. The impact of DFT-D, M05-2X, and MP2 functionals on interaction energy were tested using various basis sets. Although different functionals and basis sets show variation in absolute IE values, the trend is consistent and does not depend on the level of the calculations. Dispersion was found important for these complexes and DFT-D shows comparable IE values with MP2 functional. The optimum and maximum cage occupancy for all the considered cages were tested on the basis of quantum chemical calculations. The maximum cage occupancy for all five considered cages (5<SUP>12</SUP>, 4<SUP>3</SUP>5<SUP>6</SUP>6<SUP>3</SUP>, 5<SUP>12</SUP>6<SUP>2</SUP>, 5<SUP>12</SUP>6<SUP>4</SUP>, and 5<SUP>12</SUP>6<SUP>8</SUP>) is one, two, two, two, and seven CO<SUB>2</SUB> molecules, respectively, and the optimum cage occupancy is one, one, one, two, and five CO<SUB>2</SUB> molecules, respectively. Thus, 5<SUP>12</SUP>6<SUP>8</SUP> cages can host up to 7 CO<SUB>2</SUB> molecules, resulting in about 32 wt %, which makes them highly promising materials

Molecular dynamics investigation on a series of HIV protease inhibitors: assessing the performance of MM-PBSA and MM-GBSA approaches

The binding free energies (&#x0394;GBind) obtained from molecular mechanics with Poisson–Boltzmann surface area (MM-PBSA) or molecular mechanics with Generalized Born surface area (MM-GBSA) calculations using molecular dynamics (MD) trajectories are the most popular procedures to measure the strength of interactions between a ligand and its receptor. Several attempts have been made to correlate the &#x0394;GBind and experimental IC50 values in order to observe the relationship between binding strength of a ligand (with its receptor) and its inhibitory activity. The duration of MD simulations seems very important for getting acceptable correlation. Here, we are presenting a systematic study to estimate the reasonable MD simulation time for acceptable correlation between &#x0394;GBind and experimental IC50 values. A comparison between MM-PBSA and MM-GBSA approaches is also presented at various time scales. MD simulations (10 ns) for 14 HIV protease inhibitors have been carried out by using the Amber program. MM-PBSA/GBSA based &#x0394;GBind have been calculated and correlated with experimental IC50 values at different time scales (0–1 to 0–10 ns). This study clearly demonstrates that the MM-PBSA based &#x0394;GBind (&#x0394;GBind-PB) values provide very good correlation with experimental IC50 values (quantitative and qualitative) when MD simulation is carried out for a longer time; however, MM-GBSA based &#x0394;GBind (&#x0394;GBind-GB) values show acceptable correlation for shorter time of simulation also. The accuracy of &#x0394;GBind-PB increases and &#x0394;GBind-GB remains almost constant with the increasing time of simulation