Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions

In silico prediction is a well-established approach to derive a general shape of an RNA molecule based on its sequence or secondary structure. This paper reports an analysis of the stereochemical quality of the RNA three-dimensional models predicted using dedicated computer programs. The stereochemistry of 1,052 RNA 3D structures, including 1,030 models predicted by fully automated and human-guided approaches within 22 RNA-Puzzles challenges and reference structures, is analysed. The evaluation is based on standards of RNA stereochemistry that the Protein Data Bank requires from deposited experimental structures. Deviations from standard bond lengths and angles, planarity or chirality are quantified. A reduction in the number of such deviations should help in the improvement of RNA 3D structure modelling approaches.

Effect of Polyphenolic Compounds of Rosa Canina (L.) Against The Acetylcholinesterase Activity of Rhopalosiphum Padi (L.) (Homoptera: Aphididae)

Rhopalosiphum padi (L.) is among the most aggressive cereal pests worldwide. The pest causes economically heavy crop loss. Chemical insecticides were used for the control of multiple insects. However, the harmful consequences of these chemical products are well known. Seeking more ecological alternatives, respect to the environment is, therefore, a necessity. The phytochemicals are known for their various biological activities of pharmaceutical and agri-food interest. Several plant species have been found to have effective bioinsecticide properties against a variety of insects. In this study, the plant Rosa canina (L.) has made the objective of an in-silico research using molecular docking by screening the inhibitory potential of its polyphenolic compounds against the enzyme acetylcholinesterase of R. padi (L.). The enzyme 3D structure was first modeled, then its stereochemical quality was validated. The result of molecular docking allowed the selection of seven phytocompounds (Ellagic acid, Dihydroquercetin, Bilobalide A, Luteolin 5-methyl ether, Rosmarinic acid, Kaempferol, and Quercetin) with binding energy lower than that of the commercial insecticide Malathion. These components showed intense links with the catalytic site key residues of the enzyme, indicating their high inhibitor potential. The environmental and health safety of these components and their bio-availability were also validated by the verification of several pharmacokinetic and ADMET criteria, suggesting the interest of the plant R. canina (L.) as promising bioinsecticide material against the pest R. padi (L.).

Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions

In silico prediction is a well-established approach to derive a general shape of an RNA molecule based on its sequence or secondary structure. This paper reports on the stereochemical quality of the RNA three-dimensional models predicted using dedicated computer programs. The stereochemistry of 1,052 RNA 3D structures, including 1,030 models predicted by fully automated and human-guided approaches within 22 RNA-Puzzles challenges and reference structures, is analysed. The evaluation is based on standards of stereochemistry, established for RNA, that the Protein Data Bank requires from deposited experimental structures. Deviations from standard bond lengths and angles, planarity or chirality are quantified. A reduction in the number of such deviations should help in the improvement of RNA 3D structure prediction accuracy.

Molecular docking analysis of flupenthixol and desmethylastemizole with the apoptotic regulator proteins CFLAR and TRAF2 linked to lung carcinoma

It is known that molecular changes in apoptotic genes due to mutation may cause disruption of apoptotic pathway resulting in an abrupt increase in cell proliferation. Therefore, it is of interest to identify compounds that could potentially replenish the changes in the apoptotic pathway, resulted from mutation. The gene network analysis using the Network Analyzer Plugin of Cytoscape (3.5.1) shows CFLAR and TRAF2 as influential genes in the apoptotic pathway. Mutation in these genes brings loss in apoptotic property of a cell and thus increases the cell proliferating activity. Thus, data on the molecular docking analysis of four natural compounds from Ottelia alismoides (L.) Pers with the two target proteins were reported. Flupenthixol and desmethylastemizole was found to be two efficient ligand molecules based on ligand-target interaction. In stereochemical quality assessment, the Ramachandran plot analysis of receptors indicates the better stereochemical characteristics for receptor-ligand interaction.

Characterization of a novel mCH3 conjugated anti-PcrV scFv molecule

Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections and death in cystic fibrosis patients. The study was conducted to evaluate the physicochemical structure, biological activity and serum stability of a recombinant anti-PcrV single chain variable antibody fragment genetically attached to the mCH3cc domain. The stereochemical properties of scFv-mCH3 (YFL001) and scFv (YFL002) proteins as well as molecular interactions towards Pseudomonas aeruginosa PcrV were evaluated computationally. The subcloned fragments encoding YFL001 and YFL002 in pET28a were expressed within the E. coli BL21-DE3 strain. After Ni–NTA affinity chromatography, the biological activity of the proteins in inhibition of PA induced hemolysis as well as cellular cytotoxicity was assessed. In silico analysis revealed the satisfactory stereochemical quality of the models as well as common residues in their interface with PcrV. The structural differences of proteins through circular dichroism spectroscopy were confirmed by NMR analysis. Both proteins indicated inhibition of ExoU positive PA strains in hemolysis of red blood cells compared to ExoU negative strains as well as cytotoxicity effect on lung epithelial cells. The ELISA test showed the longer serum stability of the YFL001 molecule than YFL002. The results were encouraging to further evaluation of these two scFv molecules in animal models.

Genome-wide Characterization Deciphers Distinct Properties of Aquaporins in Six Phytophthora species

Background: Aquaporins, also known as major intrinsic proteins (MIPs), facilitate the membrane diffusion of water and some other small solutes. The role of MIPs in plant physiological processes is established and now their roles in plant-pathogen interactions are getting more attention. Objective: To investigate the evolution, diversity, and structural insights of Phytophthora MIPs (PhyMIPs) and to compare them to those in other domains of life. Methods: Bioinformatics approaches were used to identify and characterize the PhyMIPs. The phylogenetic analysis was done with MEGA7.0 using maximum likelihood method. The prediction of transmembrane α-helices was done by using SOSUI and TMpred servers, and that of subcellular localization was performed with WoLF PSORT and Cello prediction system. The structure of PhyMIP genes was predicted by GeneMark.hmm ES-3.0 program. The 3D homology models were generated using the Molecular Operating Environment software and the stereochemical quality of the templates and models was assessed by PROCHECK. The PoreWalker server was used to detect and characterize PhyMIP channels from their 3D structural models. Results: Herein, we identified 17, 24, 27, 19, 19, and 22 full-length MIPs, respectively, in the genomes of six Phytophthora species, P. infestans, P. parasitica, P. sojae, P. ramorum, P. capsici,and P. cinnamomi. Phylogenetic analysis showed that the PhyMIPs formed a completely distinct clade from their counterparts in other taxa and were clustered into nine subgroups. Sequence and structural properties indicated that the primary selectivity-related constrictions, including aromatic arginine (ar/R) selectivity filter and Froger's positions in PhyMIPs were distinct from those in other taxa. The substitutions in the conserved Asn-Pro-Ala motifs in loops B and E of many PhyMIPs were also divergent from those in other taxonomic domains. The group-specific consensus sequences/motifs deciphered in different loops and transmembrane α-helices of PhyMIPs were distinct from those in plants, animals, and other microbes. Conclusion: This study represents PhyMIPs with distinct evolutionary and structural properties, and the data collectively indicates that PhyMIPs might have novel functions.

In silico study examining new phenylpropanoids targets with antidepressant activity

Background: Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission. Objective: To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity. Results and Conclusion: We conducted an in silico molecular modeling study, based on homology, to determine the three-dimensional structure the 5-hydroxytryptamine 2A receptor (5-HT2AR), then performed molecular docking studies and examined the predisposition for cytotoxicity risk among identified molecules. We obtained a model for 5-HT2AR homology, with satisfactory results, indicating the good stereochemical quality of the model. The phenylpropanoid 4- allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.

A new insight for the screening of potential β-lactamase inhibitors

The β-lactamase produces by Aeromonas hydrophila which enables to hydrolyze and inactivate β-lactam ring of antibiotics. The homology modeling was used to generate the 3-D model of β-lactamase by using known template 3-D structure. The stereochemical quality and torsion angle of 3-D model were validated. Total eleven effective drugs have been selected and targeted the active amino acid residues in β-lactamase. The drugs were derivative of β-lactam ring antibiotics and screening was made by docking. Out of 11 drugs, 3 drugs (Ampicillin, Astreonam and Sultamicillin) were found to be more potent on the basis of robust binding energy between protein-drug interactions. Additionally, homology of β-lactamase of A. hydrophila resembled with other pathogenic bacteria that used for phylogeny analysis. These findings suggest a new insight for better understanding and useful for designing of novel potent drugs.