Design,synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1

The design, synthesis, and structure–activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.     

Phenotypic and molecular characterisation of efficient nitrogen-fixing Azotobacter strains from rice fields for crop improvement

Biological nitrogen fixation (BNF) is highly effective in the field and potentially useful to reduce adverse effects chemical fertilisers. Here, Azotobacter species were selected via phenotypic, biochemical and molecular characterisations from different rice fields. Acetylene reduction assay of Azotobacter spp. showed that Azotobacter vinelandii (Az3) fixed higher amount of nitrogen (121.09 nmol C₂H₄?mg^-1 bacteria h^-1). Likewise, its plant growth functions, viz. siderophore, hydrogen cyanide, salicylic acid, IAA, GA₃, zeatin, NH₃, phosphorus solubilisation, ACC deaminase and iron tolerance, were also higher. The profile of gDNA, plasmid DNA and cellular protein profile depicted inter-generic and inter-specific diversity among the isolates of A. vinelandii. The PCR-amplified genes nifH, nifD and nifK of 0.87, 1.4 and 1.5 kb , respectively, were ascertained by Southern blot hybridisation in isolates of A. vinelandii. The 16S rRNA sequence from A. vinelandii (Az3) was novel, and its accession number (JQ796077) was received from NCBI data base. Biofertiliser formulation of novel A. vinelandii isolates along with commercial one was evaluated in rice (Oriza sativa L. var. Khandagiri) fields. The present finding revealed that treatment T4 (Az3) (A. vinelandii) are highly efficient to improved growth and yield of rice crop.     

Configurational-bias sampling technique for predicting side-chain conformations in proteins

Prediction of side-chain conformations is an important component of several biological modeling applications. In this work, we have developed and tested an advanced Monte Carlo sampling strategy for predicting side-chain conformations. Our method is based on a cooperative rearrangement of atoms that belong to a group of neighboring side-chains. This rearrangement is accomplished by deleting groups of atoms from the side-chains in a particular region, and regrowing them with the generation of trial positions that depends on both a rotamer library and a molecular mechanics potential function. This method allows us to incorporate flexibility about the rotamers in the library and explore phase space in a continuous fashion about the primary rotamers. We have tested our algorithm on a set of 76 proteins using the all-atom AMBER99 force field and electrostatics that are governed by a distance-dependent dielectric function. When the tolerance for correct prediction of the dihedral angles is a <20 degrees deviation from the native state, our prediction accuracies for chi1 are 83.3% and for chi1 and chi2 are 65.4%. The accuracies of our predictions are comparable to the best results in the literature that often used Hamiltonians that have been specifically optimized for side-chain packing. We believe that the continuous exploration of phase space enables our method to overcome limitations inherent with using discrete rotamers as trials.     

CIRSE: a solvation energy estimator compatible with flexible protein docking and design applications

We present the Coordinate Internal Representation of Solvation Energy (CIRSE) for computing the solvation energy of protein configurations in terms of pairwise interactions between their atoms with analytic derivatives. Currently, CIRSE is trained to a Poisson/surface-area benchmark, but CIRSE is not meant to fit this benchmark exclusively. CIRSE predicts the overall solvation energy of protein structures from 331 NMR ensembles with 0.951+/-0.047 correlation and predicts relative solvation energy changes between members of individual ensembles with an accuracy of 15.8+/-9.6 kcal/mol. The energy of individual atoms in any of CIRSE's 17 types is predicted with at least 0.98 correlation. We apply the model in energy minimization, rotamer optimization, protein design, and protein docking applications. The CIRSE model shows some propensity to accumulate errors in energy minimization as well as rotamer optimization, but these errors are consistent enough that CIRSE correctly identifies the relative solvation energies of designed sequences as well as putative docked complexes. We analyze the errors accumulated by the CIRSE model during each type of simulation and suggest means of improving the model to be generally useful for all-atom simulations.     

Application of Oligonucleoside Methylphosphonates in the Studies on Phosphodiester Hydrolysis by Serratia Endonuclease

Abstract

The endonuclease from Serratia marcescens is a non-specific enzyme that cleaves single and double stranded RNA and DNA. It accepts a phosphorylated pentanucleotide as a minimal substrate which is cleaved in the presence of Mg²⁺ at the second phosphodiester linkage. The present study is aimed at understanding the role of electrostatic and hydrogen bond interactions in phosphodiester hydrolysis. Towards this objective, six pentadeoxyadenylates with single stereoregular methylphosphonate substitution within this minimal substrate (2a-4b) were synthesized following a protocol described here. These modified oligonucleotides were used as substrates for the Serratia nuclease. The enzyme interaction studies revealed that the enzyme failed to hydrolyze any of the methylphosphonate analogues suggesting the importance of negative charge and/or hydrogen bond acceptors in binding and cleavage of its substrate. Based on these results and available site-directed mutagenesis as well as structural data, a model for nucleic acid binding by Serratia nuclease is proposed.     

Role of heavy metal resistant Ochrobactrum sp. and Bacillus spp. strains in bioremediation of a rice cultivar and their PGPR like activities

The present study demonstrates the metal toxicity ameliorating and growth promoting abilities of three different bacterial isolates when applied to rice as host plant. The three bacterial strains included a cadmium resistant Ochrobactrum sp., a lead resistant Bacillus sp. and an arsenic resistant Bacillus sp. designated as CdSP9, PbSP6, and AsSP9, respectively. When these isolates were used as inocula applied to metal-treated rice plants of variety Satabdi, the germination percentage, relative root elongation (RRE), amylase and protease activities were increased. The toxic effect of metal was reduced in presence of these bacteria. The overall biomass and root/shoot ratio were also enhanced by bacterial inoculation. Hydroponic studies showed that the superoxide dismutase (SOD) activity and malondialdehyde (MDA) level, which had been increased in the presence of metal stress in rice roots, were lowered by the bacterial inoculation. In addition, all three strains were 1-aminocyclopropane-1-carboxylate (ACC) deaminase and catalase positive, whereas siderophore producing ability was lacking in PbSP6. However, both PbSP6 and AsSP9 were protease positive and could hydrolyse starch. The data indicate that these bacteria have promise for bioremediation as well as for plant growth promotion.     

Localized Plasmonic Photothermal Therapy as a Life-saving Treatment Paradigm for Hospitalized COVID-19 Patients

Plasmonics - Lung failure is the main reason for mortality in COVID-19 patients, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drug has been clinically...