Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes, of which enhancer of zeste homolog 2 (EZH2) acts as tumor suppressor. Overexpression of EZH2 results in hyper activation found in a variety of cancer. Point mutation on two important residues were induced and the results were compared between the wild type and mutant EZH2. The mutation of Y641 and A677 present in the active region of the protein alters the interaction of the top ranked compound with the newly modeled binding groove of the SET domain, giving a GLIDE score of −12.26 kcal/mol, better than that of the wild type at −11.664 kcal/mol. In depth analysis were carried out for understanding the underlying molecular mechanism using techniques viz. molecular dynamics, principal component analysis, residue interaction network and free energy landscape analysis, which showed that the mutated residues changed the overall conformation of the system along with the residue-residue interaction network. The insight from this study could be of great relevance while designing new compounds for EZH2 enzyme inhibition and the effect of mutation on the overall binding mechanism of the system.

Ebola virus is a single-stranded, negative-sense RNA virus that causes severe hemorrhagic fever in humans and non-human primates. This virus is unreceptive to a large portion of the known antiviral drugs, and there is no valid treatment as on date for disease created by this pathogen. Looking into its ability to create a pandemic scenario across globe, there is an utmost need for new drugs and therapy to combat this life-threatening infection. The current study deals with the evaluation of the inhibitory activity of flavonoids against the four selected Ebola virus receptor proteins, using in silico studies. The viral proteins VP40, VP35, VP30 and VP24 were docked with small molecules obtained from flavonoid class and its derivatives and evaluated on the basis of energetics, stereochemical considerations and pharmacokinetic properties to identify potential lead compounds. The results showed that both top-ranking screened flavonoids, i.e., Gossypetin and Taxifolin, showed better docking scores and binding energies in all the EBOV receptors when compared to those of the reported compound. All the screened flavonoids have known antiviral activity, acceptable pharmacokinetic properties and are being used on human and thus can be taken as anti-Ebola therapy without the time lag for clinical trial.

Deficiency of necessary macronutrients, i.e., Potassium (K), Magnesium (Mg), Nitrogen (N), Phosphorus (P), and Sulfate (S) in the soil leads to a reduction in plant growth and yield, which is a result of changes in expression level of various genes. This study was performed to identify the differentially expressed genes and its associated metabolic pathways occurred in soil grown wheat root samples excavated from the control and treated fields. To identify the difference in gene expression levels due to deficiency of the said nutrients, a transcriptomic, meta-analysis was performed on array expression profile data. A set of 435 statistically significant probes encoding 398 Nutrient Deficiency Response Genes (NRGs) responding at-least one nutrients deficiency (ND) were identified. Out of them 55 NRGs were found to response to minimum two ND. Singular Enrichment Analysis (SEA) predicts ontological based classifications and functional analysis of NRGs in different cellular/molecular pathways involved in root development and growth. Functional annotation and reaction mechanism of differentially expressed genes, proteins/enzymes in the different metabolic pathway through MapMan analysis were explored. Further the meta-analysis was performed to revels the active involvement each NRGs in distinct tissues and their comparative potential expression analysis in different stress conditions. The study results in exploring the role of major acting candidate genes such as Non-specific serine/threonine protein kinase, Xyloglucan endotransglucosylase/hydrolase, Peroxides, Glycerophosphoryl diester phosphodiesterase, S-adenosylmethionine decarboxylase proenzyme, Dehydrin family proteins, Transcription factors, Membrane Proteins, Metal binding proteins, Photosystem proteins, Transporter and Transferase associated in different metabolic pathways. Finally, the differences of transcriptional responses in the soil-grown root of T. aestivum cv. and in-vitro grown model plants under nutrients deficiency were summarized.

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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.

Protein phosphorylation is an important mechanism that implicates in physiology of any organism including parasitic protozoa. Metallic protein Ser/Thr protein phosphatase 5 (PP5) controls various cellular signaling pathways of Plasmodium falciparum. The structure and inhibitory mechanism of PP5 in P. falciparum is not known. In fact, no experimental structural data are available for P. falciparum Ser/Thr protein phosphatase 5 (PfPP5) till date. Hence, we have proposed computer-generated model of catalytic subunit of PfPP5 and its inhibitory mechanism was analyzed. A set of 42 known natural inhibitors of protein phosphate family were docked against metal-binding catalytic site of PfPP5 and we found that cantharidin and its derivatives shows better binding energy among them. Similarity search was performed by taking these compounds as lead compounds against PubChem and ChemBank. The search result provides 3703 similar compounds; out of which 2245 qualified the Lipinski rule of five. Further, virtual screening of these compounds was performed and selected top 25 were selected on the basis of binding energy. In continuation, rigid and flexible docking of these screened compounds was performed to get the insight of interactions. Finally, top 5 compounds were verified for ADMET properties, and then, all are subjected to MD simulations for 25 ns in order to validate their stability. Compounds CBI: 3554182, CID: 23561913, and CID: 21168680 showed most stable binding, although some of hydrogen bonds pairing varied throughout simulation. These finding would be helpful to the medicinal chemists for the development of antimalarial drugs to combat this deadly disease.

Bromodomains (BRDs) are the epigenetic proteins responsible for transcriptional regulation through its interaction with methylated or acetylated histone residues. The lysine residues of Bromodomain-1 (BD1) of Brd4 undergo ε-N-Acetylation posttranslational modifications to control transcription of genes. Due to its role in diverse cellular functions, Brd4 of bromodomain family, was considered as a prominent target for many diseases such as cancer, obesity, kidney disease, lung fibrosis, inflammatory diseases, etc. In this study, an attempt has been made to screen compounds from flavonoids and extended flavonoids libraries targeting acetylated lysine (K) binding site of BD1 of Brd4 using docking and molecular dynamics simulations. Two different docking programs AutoDock and Glide were used to compare their suitability for the receptor. Interestingly, in both the docking programs, the screened flavonoids have occupied the same binding pocket confirming the selection of active site. Further the MMGBSA binding free energy calculations and ADME analysis were carried out on screened compounds to establish their anti-cancerous properties. We have identified a flavonoid which shows docking and Glide e-model score comparatively much higher than those of already reported known inhibitors against Brd4. The protein-ligand complex with top-ranked flavonoid was used for dynamics simulation study for 50 ns in order to validate its stability inside the active site of Brd4 receptor. The results provide valuable information for structure-based drug design of Brd4 inhibitors.

Cereal grain bread wheat (T. aestivum) is an important source of food and belongs to Poaceae family. Hypothetical proteins (HPs), i.e., proteins with unknown functions, share a substantial portion of wheat proteomes and play important roles in growth and physiology of plant system. Several functional annotations studies utilizing the protein sequences for characterization of role of individual protein in physiology of plant systems were being reported in recent past. In this study, an integrated pipeline of software/servers has been used for the identification and functional annotation of 124 unique HPs of T. aestivum considering available data in NCBI till date. All HPs were broadly annotated, out of which functions of 77 HPs were successfully assigned with high confidence level. Precisely functional annotation of remaining 47 HPs is also characterized with low confidence. Several latest versions of protein family databases, pathways information, genomics context methods and in silico tools were utilized to identify and assign function for individual HPs. Annotation result of several HPs mainly belongs to cellular protein, metabolic enzymes, binding proteins, transmembrane proteins, transcription factors and photosystem regulator proteins. Subsequently, functional analysis has revealed the role of few HPs in abiotic stress, which were further verified by phylogenetic analysis. The functionally associated proteins with each of above-mentioned abiotic stress-related proteins were identified through protein-protein interaction network analysis. The outcome of this study may be helpful for formulating general set pipeline/protocols for a better understanding of the role of HPs in physiological development of various plant systems.