Computational analysis of the structural basis of ligand binding to the crustacean retinoid X receptor.

Homodimerization of the retinoid X receptor (RXR) occurs upon binding of ligands to the receptor, but little is known about structural mechanisms involved in RXR ligand binding. In the present study, binding of known ligands (5-Hydroxytryptamine, dopamine and naloxone) to the Celuca pugilator RXR was modeled computationally using the human RXR-α as a homology template. Docking scores calculated for these ligands showed reasonably good binding interactions to C. pugilator RXR. Furthermore, RXR is the receptor that mediates the different activities of neurotransmitters and opioid against naloxone in crustaceans and possibly other species. These results indicate that 5-hydroxytryptamine and naloxone might have similar functions. These also results suggest a 3-D model of C. pugilator RXR that describes the binding of ligands at a single RXR receptor binding site and offers further insight into the binding of structurally diverse ligands to this receptor. Further, computational studies showed that crustacean RXRs might be closer to vertebrate RXR than to insect RXR. The predicted binding models for C. pugilator RXR may allow for better design of experimental studies, such as site-directed mutagenesis and affinity labeling studies that may yield valuable information concerning structure-activity relationship studies of RXR and its ligands.

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies.

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.

3D-QSAR and molecular docking studies of 1,3,5-triazene-2,4-diamine derivatives against r-RNA: novel bacterial translation inhibitors.

Aminoglycoside mimetics inhibit bacterial translation by interfering with the ribosomal decoding site. To elucidate the structural properties of these compounds important for antibacterial activity, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to a set of 56 aminoglycosides mimetics. The successful CoMFA model yielded the leave-one-out (LOO) cross-validated correlation coefficient (q(2)) of 0.708 and a non-cross-validated correlation coefficient (r(2)) of 0.967. CoMSIA model gave q(2)=0.556 and r(2)=0.935. The CoMFA and CoMSIA models were validated with 36 test set compounds and showed a good r(pred)(2) of 0.624 and 0.640, respectively. Contour maps of the two QSAR approaches show that electronic effects dominantly determine the binding affinities. These obtained results were agreed well with the experimental observations and docking studies. The results not only lead to a better understanding of structural requirements of bacterial translation inhibitors but also can help in the design of novel bacterial translation inhibitors.

CoMFA and docking studies on triazolopyridine oxazole derivatives as p38 MAP kinase inhibitors.

With the objective to design new chemical entities with enhanced inhibitory potencies against p38 MAP alpha kinase, the 3D-QSAR and Comparative Molecular Field Analysis (CoMFA) studies were carried out on triazolopyridine oxazole compounds as inhibitors of these kinase is presented here. The developed model gave q(2) value of 0.707 and r(2) value of 0.942 for CoMFA. The high leave-one-out (LOO) cross-validated correlation coefficient q(2) reveals that the model is a useful tool for the prediction of test set of 19 compounds that were not included in the training set of 55 compounds. The results not only lead to better understanding of structural requirements of p38 alpha inhibitors but also can help in the design of new potent inhibitors. The binding mode of the compounds at the active site of p38 MAP alpha kinase was explored using Glide docking program and hydrogen-bonding interactions were observed between the inhibitors and the target. The details of amino acid interactions of the active site are discussed briefly and correlated with the contour plots.

Comparative molecular field analysis of quinoline derivatives as selective and noncompetitive mGluR1 antagonists.

A 3D- QSAR model os Comparative Molecular Field Analysib (CoMFA) of 45 quinoline derivatives as metaborropic glutamate receptor subtype 1 (mGluR1) inhibitors wew investigated. The CoMFA analysis provided a model with q(2) value of 0.827 and r(2) value of 0.990, in which q(2) value of 0.827 and an r(2) value of 0.990, in which the good correlation between the inhibitory activities and the steric and electrostatic molecular field around the analoques was observed. The predictive ability of the models was validated using the set of 12 compounds that were not included in the training set of 33 compounds. These results provided further understanding of the relationship between the structural features of quinolone derivatives and its activities, which should be applicable to design and find new potential mGluR1 inhibitors.

Effect of various substrates on the growth and quality of mushrooms.

The effect of different biowastes such as paddy straw, sorghum straw, sugarcane molasses, saw dust and paper waste on the growth and biochemical constituents of oyster mushroom (Pleurotus florida) was studied. Favourable conditions were created to attain the maximum yield of mushrooms. The results reveled that mushroom growth was better in paddy straw followed by sugarcane molasses and least in wood saw dust and paper waste. The growth of mushrooms may be coincided with type of substrates used that leads to tremendous utilization of nutrients in the biowastes. The results further indicated that the biometric parameters such as fresh weight, dry weight and dry matter accumulation and biochemical constituents such as total sugars, protein, amino acids and lipids were also found to be higher in mushrooms grown in paddy straw followed by sugarcane molasses and least in wood saw dust and paper waste. The microelements such as phosphorous, potassium calcium and magnesium were also found to be higher in mushrooms grown in paddy straw when compared to the other substrates.