Computational methods have driven the rapid identification of tobacco microRNAs (miRNAs) from tissue-specific sequence data and witnessed success in associating miRNAs in response to stress, ...pollutants, viral infection and resistance, and cigarette smoking. Although tobacco exerted medicinal properties through phytochemicals, the role of its miRNAs in regulating tobacco and human genes and related functional implications is not elucidated thoroughly. In this present study, we have identified new and homologous miRNAs using a rigorous workflow of miRNA derivation and target prediction upon a comprehensive collection of tobacco expressed sequence tags and charted its putative roles in gene regulation via inter and intraspecies relationships. Current, computational approach have identified a total of 38 mature miRNAs comprising 31 tobacco-specific miRNAs from plant homologous families, and 7 new miRNA candidates. These seven new miRNAs were studied for tobacco target gene prediction in which most of them encode innate immunity, defense mechanism, plant development, F-box/Leucine rich-repeat protein and other protein kinases. Two out of these seven miRNAs have passed the updated emphasized criteria namely nta-miR403 and nta-miR8036. Interestingly, the workflow succeeded in establishing an intraspecies relationship by distinguishing the molecular targets already known in tobacco and homologous plants. Interspecies relationship between 38 tobacco miRNAs upon human transcriptome data revealed the most significant target CCDC88c (DAPLE) with perfect seed pairing of miR-156, regulating non-canonical WNT signaling pathways in cancer progression and metastasis. These findings may add to existing knowledge of impacting canonical WNT/β-catenin pathways. These decisive findings hold a strong clue for promoting tobacco miRNAs research and outlined the prediction of conserved miRNAs and their functions in inter and intraspecies relationships.
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•In-silico identification of 31 known and 7 new miRNAs in Nicotiana tabacum (N. tabacum).•Revealed the 7 new miRNAs’ plant specific role in immunity, defence and development.•First report of intra and interspecies relationship using N. tabacum miRNAs.•Unraveling the possible role of ‘nta-miR156 and Human CCDC88c (DAPLE) interaction’ in cancer metastasis.•Introducing two new miRNAs namely nta-miR403 and nta-miR8036 with updated emphasized criteria.
Murraya koenigii (Linn.) Spreng, commonly known as curry leaf tree, is popular as a condiment and spice among Asian countries. Ethnobotanical studies suggest that certain phytochemicals in different ...parts of the plant are involved in anti-inflammatory, anti-oxidant and anti-cancer activities. There is a knowledge gap in connecting the ethnobotanical applications of M. koenigii, identification of chief phytochemicals through computational approaches and and evaluation of phytochemical's effect on cancer cell lines. We present here a comprehensive study to identify the phytochemicals responsible for anti-inflammation using random forest (RF) models, the interactions with COX-1 and COX-2 enzymes using molecular docking, dynamics simulation and free energy calculations. The RF models prioritised four phytochemicals viz. girinimbine, murrayanine, murrastinine-B and mukolidine with COX-1 and COX-2 binding potential. These phytochemicals developed key contacts with COX targets which were largely retained in the trajectories of the dynamics simulations. Phytochemicals ranking based on the binding free energy suggested that girinimbine (a carbazole alkaloid) is selective towards COX-2 supported by the experimental studies on COX anti-inflammation. Cytotoxicity assessment on the breast cancer cell line MDA-MB-231 illustrated that the presence of this phytochemical in root, stem and leaf (IC
50
value: 0.006 µg/ml) parts highlight its role as a COX-2 inhibitor.
Hook is a perennial Himalayan medicinal herb of the Rosaceae family. The present study aimed to evaluate biological activities such as the antioxidant, antibacterial, and anticancer activities of ...roots and shoots of
and its synergistic antibacterial activity with antibacterial drugs. Folin-Ciocalteau and aluminium chloride methods were used for the calculation of total phenolic (TPC) and flavonoid content (TFC). A DPPH radical scavenging assay and broth dilution method were used for the determination of the antioxidant and antibacterial activity of the root and shoot extracts of
. Cytotoxic activity was determined using a colorimetric MTT assay. Further, phytochemical characterization of the root and shoot extracts was performed using the Gas chromatography-mass spectrophotometry (GC-MS) method. The TPC and TFC were found to be higher in the methanolic root extract of
. The methanolic shoot extract of
showed good antioxidant activity, while then-hexane root extract of
showed strong cytotoxic activity against tested SK-MEL-28 cells. Subsequently, in silico molecular docking studies of the identified bioactive compounds predicted potential anticancer properties. This study can lead to the production of new herbal medicines for various diseases employing
, leading to the creation of new medications.
Rheumatoid arthritis (RA) is an autoimmune disorder that causes chronic inflammation with periodic bursts of activity in multiple synovial joints which lead to irreversible damage of cartilage and ...bone. Although several drugs that reduce inflammation are used for the treatment of RA, they are often associated with side effects. Therefore, the development or identification of a drug with no side effects or reduced side effects is desirable. Protein arginine deiminases (PADs), a set of key enzymes to trigger autoimmune response necessary for the development of RA, can be targeted for the treatment of RA. In the present study, we had developed a pharmacophore model for PAD type 4 (PAD4) protein comprising single aromatic and three hydrogen acceptor groups. Pharmacophore-based virtual screening upon ZINC database mapped several hits which were subsequently reduced by molecular docking with PAD4 protein structure. The best-scoring two ligands (Zinc_00525911 and Zinc_01225171) selected based on docking energy, pharmacophore fitness, and topology among the hits were further validated using molecular dynamics simulation for 10 ns. These two ZINC hits established interactions with key amino acid residues of PAD4 including H-bonds with Arg 372, Arg 374, Asp 350, and His 471 residues. These prioritized hits can be further tested in the in vitro and in vivo models of RA.
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•PLHINT – uses knowledge gained from native-like dock poses.•Uses multiple protein-ligand complexes to derive H bond patterns and combinations.•Recovers poor and random virtual ...screening results of genetic algorithm-based docking programs.•Enrich potential compounds at the top ranks of the database by PLHINT scoring.
The tendency of docking scoring functions to generate crystal close conformations of ligands bound to protein structures face limitations in not reproducing the exact crystal intermolecular contacts in dock poses. Intermolecular H bond contacts enumerated at the protein-docked ligand interface can be used to train scoring models and improve virtual screening performance. There is a need to incorporate additional knowledge of protein-ligand H bond contacts in extension to crystal contacts from docking solutions within the reproducibility efficiency of the docking program. A computational approach PLHINT (Protein-ligand H bond interaction pattern) is presented here which extracts intermolecular H bond interactions from native-like docked ligand poses, transform into the scoring scheme and apply over the virtual screening results of database molecules. The basic premise of the PLHINT approach is to score the most observed H bond patterns with the high score to achieve high recovery rates. Tested on ten diverse DUD-E benchmark datasets, the approach has demonstrated better overall performance and ligand enrichment competency over virtual screening results generated by three genetic algorithm-based docking programs viz. AutoDock Vina, FlexAID and PLANTS. Furthermore, the approach has successfully recovered the poor and random virtual screening results with better enrichments.
Structure-based models to understand the transport of small molecules through biological membrane can be developed by enumerating intermolecular interactions of the small molecule with a biological ...membrane, usually a dimyristoylphosphatidylcholine (DMPC) monolayer. This ADME (absorption, distribution, metabolism, and excretion) property based on Madin-Darby Canine Kidney (MDCK) cell line demonstrates intestinal drug absorption of small molecules and correlated to human intestinal absorption which acts as a determining factor to forecast small-molecule prioritization in drug-discovery projects. We present here the development of MDCKpred web-tool which calculates MDCK permeability coefficient of small molecule based on the regression model, developed using membrane-interaction chemical features. The web-tool allows users to calculate the MDCK permeability coefficient (nm/s) instantly by providing simple descriptor inputs. The chemical-interaction features are derived from different parts of the DMPC molecule viz. head, middle, and tail regions and accounts overall intermolecular contacts of the small molecule when passively diffused through the phospholipid-rich biological membrane. The MDCKpred model is both internally (R
2
= .76;
= .68; R
train
= .87; R
test
= .69) and externally (R
ext
= .55) validated. Furthermore, we used natural molecules as application examples to demonstrate its utility in lead exploration and optimization projects. The MDCKpred web-tool can be accessed freely at
http://www.mdckpred.in
. This web-tool is designed to offer an intuitive way of prioritizing small molecules based on calculated MDCK permeabilities.
Several studies documented the ameliorative effects of curcumin which plays a pivotal role in radical scavenging activities. It also participates in various cellular pathways and interacts with ...multiple targets. In the present study, we investigated the ameliorative effect of curcumin upon chromosomal genotoxicity induced by cyclosporine, an immunosuppressant, using in vitro approaches. A plausible mechanism of how curcumin mitigates the genotoxic implications of cyclosporine was ascertained using in silico tools. We observed that the curcumin reduces the genotoxic consequences made by cyclosporine upon cell cycle checkpoints and associated chromosomal/DNA manifestations. In addition, we presented the mechanistic details of curcumin interaction with various biomacromolecule types using docking experiments which showed that the possible radical scavenging activities can only be emerged by inducing the expression of antioxidant enzymes, supported by available experimental evidences. We anticipate that the induction of antioxidant enzymes by curcumin would activate Nrf2-Keap1 pathway as the plausible mechanism to exert anti-inflammatory response as demonstrated in renal epithelial cells.
Recent technological breakthroughs in medicinal chemistry arena had ameliorated the perspectives of quantitative structure-activity relationship (QSAR) methods. In this direction, we developed a ...group-based QSAR method based on pharmacophore-similarity concept which takes into account the 2D topological pharmacophoric descriptors and predicts the group-specific biological activities. This activity prediction may assist the contribution of certain pharmacophore features encoded by respective fragments toward activity improvement and/or detrimental effects. We termed this method as pharmacophore-similarity-based QSAR (PS-QSAR) and studied the activity contribution of fragments from 3-hydroxypyridinones derivatives possessing antimalarial activities.
Tomato leaf curl disease (ToLCD) is manifested by yellowing of leaf lamina with upward leaf curl, leaf distortion, shrinking of the leaf surface, and stunted plant growth caused by tomato leaf curl ...virus (ToLCV). In the present study, using computational methods we explored the evolutionary and molecular prospects of viral coat protein derived from an isolate of Vadodara district, Gujarat (ToLCGV-Vad), India. We found that the amino acids in coat protein required for systemic infection, viral particle formation, and insect transmission to host cells were conserved amongst Indian strains. Phylogenetic studies on Indian ToLCV coat proteins showed evolutionary compatibility with other viral taxa. Modeling of coat protein revealed a topology similar to characteristic Geminate viral particle consisting of antiparallel β-barrel motif with N-terminus α-helix. The molecular interaction of coat protein with the viral DNA required for encapsidation and nuclear shuttling was investigated through sequence- and structure-based approaches. We further emphasized the role of loops in coat protein structure as molecular recognition interface.
Enormous caspase-3-non-peptide crystal structures have been developed to study the structural basis of caspase-3 enzyme inhibition using active site directed small molecular design. These complexes ...have not been explored thoroughly to decipher the essential non-covalent interactions made by crystal ligands. We present here a multi-level analysis of these caspase-3 complexes using structure-based pharmacophore approach wherein numerous candidate pharmacophore hypotheses were assessed for its ability to cover available caspase-3 small molecular inhibitor dataset. The reliability of the resultant pharmacophores was evaluated using three different validation sets comprising focussed caspase-3 inhibitors, focussed + random decoys, and focussed + structurally similar random decoys and its performance was measured by the Güner-Henry (GH) scoring and enrichment statistics. Furthermore, the effect on excluded volumes toward caspase-3 inhibitors mapping was investigated by an iterative deletion in the structure-based models and created optimal structure-based pharmacophore models to enable effective design of caspase-3 small molecular inhibitor design.
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•Multi-level structure-based pharmacophore modelling of caspase-3 crystal structures.•Decipher prominent non-covalent interactions of caspase-3-small molecule inhibitors.•Prioritized essential pharmacophore features mapped available inhibitor dataset.•Performance assessment using three distinct validation sets and metrics.•Comprehensive analysis of excluded volumes for caspase-3 inhibition.
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