sysbioweb

PROcket, an Efficient Algorithm to Predict Protein Ligand Binding Site

PROcket, an Efficient Algorithm to Predict Protein Ligand Binding Site

Semwal R., Aier I., Varadwaj P.K., Antsiperov S. (2019) PROcket, an Efficient Algorithm to Predict Protein Ligand Binding Site. In: Rojas I., Valenzuela O., Rojas F., Ortuño F. (eds) Bioinformatics and Biomedical Engineering. IWBBIO 2019. Lecture Notes in Computer Science, vol 11465. Springer, Cham

DOI: https://doi.org/10.1007/978-3-030-17938-0_40

Abstract: To carry out functional annotation of proteins, the most crucial step is to identify the ligand binding site (LBS) information. Although several algorithms have been reported to identify the LBS, most have limited accuracy and efficiency while considering the number and type of geometrical and physio-chemical features used for such predictions. In this proposed work, a fast and accurate algorithm “PROcket” has been implemented and discussed. The algorithm uses grid-based approach to cluster the local residue neighbors that are present on the solvent accessible surface of proteins. Further with inclusion of selected physio-chemical properties and phylogenetically conserved residues, the algorithm enables accurate detection of the LBS. A comparative study with well-known tools; LIGSITE, LIGSITECS, PASS and CASTptool was performed to analyze the performance of our tool. A set of 48 ligand-bound protein structures from different families were used to compare the performance of the tools. The PROcket algorithm outperformed the existing methods in terms of quality and processing speed with 91% accuracy while considering top 3 rank pockets and 98% accuracy considering top 5 rank pockets.

Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Current Alzheimer Research, Volume 16, Number 2, 2019, pp. 116-127(12)

DOI: https://doi.org/10.2174/1567205016666181212155147

Abstract:

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’.

Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays.

Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do.

Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

Structure-based drug designing and identification of Woodfordia fruticosa inhibitors targeted against heat shock protein (HSP70-1) as suppressor for Imiquimod-induced psoriasis like skin inflammation in mice model

Structure-based drug designing and identification of Woodfordia fruticosa inhibitors targeted against heat shock protein (HSP70-1) as suppressor for Imiquimod-induced psoriasis like skin inflammation in mice model

Materials Science and Engineering: CVolume 95, 1 February 2019, Pages 57-71

DOI: https://doi.org/10.1016/j.msec.2018.10.061

Abstract: Heat shock proteins (HSPs) emerged as a therapeutic target and it was observed that inhibition of HSP70-1 plays a pivotal role in the management of psoriasis. In-silico investigation involving techniques like molecular docking and molecular dynamics (MD) simulation analysis was performed against HSP70-1. Further, anti-psoriatic activity of bioactive immunomodulatory compounds present in ethanolic extract of Woodfordia fruticosa flowers (Wffe) using combination of bioinformatics together with ethnopharmacological approach has been explored in this study. Myricetin (−8.024), Quercetin (−7.368) and Ellagic acid (−7.311) were the top three compounds with minimum energy levels as well as high therapeutic value/ADMET as compared to currently available marketed anti-psoriatic drug Tretinoin (−7.195). ADMET prediction was used to screen ligands for drug-likeness and efficacy. Further, biogenically Woodfordia fruticosa gold nanoparticles (WfAuNPs) were synthesized and characterized by UV–Visible Spectroscopy (UV–vis), Dynamic Light Scattering (DLS), Zeta Potential, X-Ray Diffraction (XRD) and High Resolution Transmission Electron Microscopy (HRTEM) techniques. Synthesized WfAuNPs observed in the size range of 10–20 nm and were used to develop WfAuNPs-Carbopol®934 ointment gel. Subsequently, the therapeutic efficacy of WfAuNPs-Carbopol® 934 was checked against 5% Imiquimod-induced psoriasis like skin inflammation. WfAuNPs-Carbopol® 934 was found to be exerting better therapeutic effect in reducing the mean DAI score (0.63 ± 0.08), serum cytokines (TNF-α, IL-22 and IL-23) levels along with reduced epidermal thickness, parakeratosis and marked decrease in the hyperproliferation of keratinocytes. Results of the study revealed that the WfAuNPs-Carbopol® 934 could be an effective alternative treatment for psoriasis in near future.

Deciphering genome-wide WRKY gene family of Triticum aestivum L. and their functional role in response to Abiotic stress

Deciphering genome-wide WRKY gene family of Triticum aestivum L. and their functional role in response to Abiotic stress

Genes & Genomics (2019) Volume 41, Issue 1, pp 79–94

DOI: https://doi.org/10.1007/s13258-018-0742-9

Abstract: WRKY transcription factors (TFs) act in regulating plant growth and development as well as in response to different stress. Some earlier studies done by individual researchers reported different wheat WRKY TFs. Although, the recently released wheat genome has opened an avenue to investigate wheat WRKYs (TaWRKY) TFs. Prime objective of this study to performed genome-wide classifications of TaWRKYs and their functional annotation. The classification of 107 individual identified characterized sequences of TaWRKY (IICS-TaWRKY) and 160 uncharacterized draft sequences of TaWRKY (UDS-TaWRKY), along with their gene structures and motifs analysis was performed. Along with comparative sequence analysis and microarray analysis was performed to mimic out TaWRKYs functions in response to different abiotic stresses, accompanied by in-vitro validation. The comparative phylogenetic analysis and estimation of Ka/Ks ratio with Triticum urartu, illustrate group based clasifications of TaWRKYs and evolutionary divergences. Furthermore, motif-based and protein-DNA interaction analysis of TaWRKYs helps to identify, their putative function in target DNA recognition sites. Subsequently, results of microarray and comparative sequence analysis provides the evidence of TaWRKYs involved in heat and/or drought stress. Further, in-vitro results validates that TaWRKY014, TaWRKY090 are found to participate in response of drought stress, whereas TaWRKY008, TaWRKY122, and WRKY45 are involved in response of heat and drought stress. These findings can be utilized in developing novel heat and drought-tolerant wheat cultivars using marker-assisted breeding and transgenic development.

Unveiling the transcriptome complexity of the High- and Low- Zinc & Iron accumulating Indian wheat (Triticum aestivum L.) cultivars

bioRxiv, February 2019

DOI: 10.1101/538819

Development of Zinc (Zn), Iron (Fe) and other minerals rich grains along with various stress tolerance and susceptible (STR) wheat genotype, will help to reduce globally spread malnutrition problem. Current study deals with transcriptome profiling of 4 high- and 3 low- Zn & Fe accumulating wheat genotypes (HZFWGs) and (LZFWGs). Functional characterization of expressed and high and low specific genes, accompanied by metabolic pathways analysis reveals, phenylpropanoid biosynthesis, and other associated pathways are mainly participating in plant stress defense mechanism in both genotypes. Chlorophyll synthesis, Zn & Fe binding, metal ion transport, and ATP-Synthase coupled transport mechanism are highly active in HZFWGs while in LZFWGs ribosomal formation, biomolecules binding activities and secondary metabolite biosynthesis. Transcripts accountable for minerals uptake and purine metabolism in HZFWGs are highly enriched. Identified transcripts may be used for marker-assisted selection and breeding to develop minerals rich crops.

A systematic assessment of statistics, risk factors, and underlying features involved in pancreatic cancer

A systematic assessment of statistics, risk factors, and underlying features involved in pancreatic cancer,

Cancer Epidemiology 58:104-110, February 2019

DOI: 10.1016/j.canep.2018.12.001.

Abstract

Pancreatic cancer remains the fourth leading cause of cancer-related death in the world, and will continue to become the number two cause of cancer-related death unless a remarkable breakthrough is achieved. With a slim chance of early diagnosis, surgery can only provide a median survival of 17-23 months. The presence of a dense stroma makes this cancer resilient to chemotherapy, with very few potent inhibitors like nab paclitaxelin available that can work in combination with chemotherapeutic agents. Survival rates, on the one hand, lie at 8.5%. Variation in types of pancreatic cancer, on the other hand, makes it notoriously difficult to come up with a practical solution for the treatment of this disease. A deeper understanding of the root cause would be beneficial for diagnosis. Advancement in the field of genomics has made the identification of novel biomarkers relatively easier. By coupling this factor with the production of suitable inhibitors, testing in large numbers can be made possible with the help of cell lines. With the combined efforts of biological knowledge and modern technology, the cure for pancreatic cancer could be at hand.

https://www.ncbi.nlm.nih.gov/pubmed/30537645