S. Usha

Bio: S. Usha is an academic researcher from Bharathiar University. The author has contributed to research in topics: Amino acid & Cytosine. The author has an hindex of 3, co-authored 7 publications receiving 18 citations. Previous affiliations of S. Usha include Bharathidasan University.

Structure-based drug design of peroxisome proliferator-activated receptor gamma inhibitors: ferulic acid and derivatives.

Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ), ligand-activated transcription factor, is a key modulator of genes considered in diabetes development as well as treatment. Adipogenesis di...

Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions.

Abstract: We have analyzed the nonbonded interactions of the structurally similar moieties, adenine and guanine forming complexes with proteins. The results comprise (a) the amino acid-ligand atom preferences, (b) solvent accessibility of ligand atoms before and after complex formation with proteins, and (c) preferred amino acid residue atoms involved in the interactions. We have observed that the amino acid preferences involved in the hydrogen bonding interactions vary for adenine and guanine. The structural variation between the purine atoms is clearly reflected by their burial tendency in the solvent environment. Correlation of the mean amino acid preference values show the variation that exists between adenine and guanine preferences of all the amino acid residues. All our observations provide evidence for the discriminating nature of the proteins in recognizing adenine and guanine.

Structure-wise discrimination of cytosine, thymine, and uracil by proteins in terms of their nonbonded interactions

Abstract: The molecular recognition and discrimination of very similar ligand moieties by proteins are important subjects in protein-ligand interaction studies. Specificity in the recognition of molecules is determined by the arrangement of protein and ligand atoms in space. The three pyrimidine bases, viz. cytosine, thymine, and uracil, are structurally similar, but the proteins that bind to them are able to discriminate them and form interactions. Since nonbonded interactions are responsible for molecular recognition processes in biological systems, our work attempts to understand some of the underlying principles of such recognition of pyrimidine molecular structures by proteins. The preferences of the amino acid residues to contact the pyrimidine bases in terms of nonbonded interactions; amino acid residue-ligand atom preferences; main chain and side chain atom contributions of amino acid residues; and solvent-accessible surface area of ligand atoms when forming complexes are analyzed. Our analysis shows that the amino acid residues, tyrosine and phenyl alanine, are highly involved in the pyrimidine interactions. Arginine prefers contacts with the cytosine base. The similarities and differences that exist between the interactions of the amino acid residues with each of the three pyrimidine base atoms in our analysis provide insights that can be exploited in designing specific inhibitors competitive to the ligands.

Importance of Fluctuating Amino Acid Residues in Folding and Binding of Proteins

Abstract: Background Conformational flexibility of proteins remains as one of the major events in protein-protein/DNA/ligand/small molecule binding to achieve its biological function in the cell. The availability of high-resolution structures of protein complexes is a valuable resource for researchers to understand the mechanisms behind such interactions and it is found that the flexibility of amino acid residues at binding sites is crucial for many important functions in the cell. Methods In this article, our statistical method (PreFRP) developed based on fluctuating amino acid residues and various amino acid indices related to flexibility/rigidity were used to study the importance of fluctuating amino acid residues in thermonucleases from pathogenic bacteria, cell penetrating peptides and intrinsically disordered proteins responsible for many neural disorders. Results The results from our analysis reveal the importance of fluctuating amino acid residues in folding and binding of proteins. The role of moderate and high fluctuating residues in themonucleases, cell penetrating peptide and disordered regions are discussed in detail. Conclusion Therefore, our analysis will help in understanding the importance of fluctuating amino acid residues in proteins which undergo a conformation change phenomenon.

Identification of oxazolo[4,5-g]quinazolin-2(1H)-one Derivatives as EGFR Inhibitors for Cancer Prevention

Abstract: Objective: Abnormal expression of EGFR (epidermal growth factor receptor) results in different types of human tumors. Quinazoline-containing derivative signify an attractive platform for EGFR inhibitors. The present study aims to discover the potential binders of a group of compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative as EGFR inhibitors. Methods: We apply multiple computational procedures, including pharmacophore-based virtual screening methods, to perform a preliminary screening against EGFR over compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative. Then, we carried a fine screening by molecular dynamics simulations, followed by free energy calculations. Results: The best pharmacophore model created has five characteristics. Three hydrogen bonds acceptors (A) and two aromatic rings (R) make up AAARR (a sequential representation of chemical features of ligands). We have performed pharmacophore-based screening with different databases like Asinex, Chembridge, Lifechemicals, Maybridge, Specs, and Zinc. Top-scoring 30 molecules were considered for performing induced fit docking. Molecular Dynamics Simulations executed for the top five ligands confirmed that throughout the simulation, the protein-ligand complexes remained stable. Conclusion: Thus, the results obtained from this research provide insights for the development of oxazolo[4,5-g]quinazoline-2(1H)-one derivative as potent EGFR inhibitors.

Inhibition of Quorum Sensing and Biofilm Formation in Chromobacterium violaceum by Fruit Extracts of Passiflora edulis.

Abstract: Chromobacterium violaceum (C. violaceum) is a Gram-negative, rod-shaped facultatively anaerobic bacterium implicated with recalcitrant human infections. Here, we evaluated the anti-QS and antibiofilm activities of ethyl acetate extracts of Passiflora edulis (P. edulis) on the likely inactivation of acyl-homoserine lactone (AHL)-regulated molecules in C. violaceum both by in vitro and in silico analyses. Our investigations showed that the sub-MIC levels were 2, 1, and 0.5 mg/mL, and the concentrations showed a marked reduction in violacein pigment production by 75.8, 64.6, and 35.2%. AHL quantification showed 72.5, 52.2, and 35.9% inhibitions, inhibitions of EPS production (72.8, 36.5, and 25.9%), and reductions in biofilm formation (90.7, 69.4, and 51.8%) as compared to a control. Light microscopy and CLSM analysis revealed dramatic reduction in the treated biofilm group as compared to the control. GC-MS analysis showed 20 major peaks whose chemical structures were docked as the CviR ligand. The highest docking score was observed for hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester bonds in the active site of CviR with a binding energy of -8.825 kcal/mol. Together, we found that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester remarkably interacted with CviR to inhibit the QS system. Hence, we concluded that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester of P. edulis could likely be evaluated for treating C. violaceum infections.

Identification of good and bad fragments of tricyclic triazinone analogues as potential PKC-θ inhibitors through SMILES–based QSAR and molecular docking

Abstract: Based on the mechanism of action of PKC-θ, the inhibition of this enzyme is considered a potential target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. In the present study, 57 structurally diverse tricyclic triazinone analogues as potential PKC-θ inhibitors has been taken into consideration for QSAR analysis through Monte Carlo optimization. QSAR models are developed using the balance of correlation method in the CORAL software with two target functions (TF1 and TF2). The models constructed with IIC are found more robust and authentic. The established QSAR model with best $$ {R}_{\mathrm{calibration}}^2 $$ = 0.9653 for split 3 is considered the topmost model. The predictabilities of the recommended QSAR model are assessed through various statistical parameters. The outlier of each model is also identified using the applicability domain (AD). The common mechanistic interpretation of the increasing and decreasing attributes has been extracted by evaluating the correlation weights of diverse structural attributes obtained in three Monte Carlo optimization runs from two splits, i.e., split 3 and 4. In the last, the result of mechanistic interpretation is validated by performing the docking studies of compounds PKC03, PKC07, PKC16, PKC25, and PKC56 in the experimental structure of protein kinase C-θ (PDB ID: 4Q9Z). The numerical value of the correlation coefficient between calculated activity and binding affinity is found 0.9597. Hence, the developed QSAR models are descriptive and predictive in nature and the results are in sound agreement with the experimental observations.

Natural Products as Sources of Multitarget Compounds: Advances in the Development of Ferulic Acid as Multitarget Therapeutic

Abstract: Nature has provided therapeutic substances for millennia, with many valuable medications derived from plant sources. Multitarget drugs become essential in the management of various disorders, including hepatic disorders, neurological disorders, diabetes, and carcinomas. Ferulic acid is a significant potential therapeutic agent, which is easily available at low cost, possesses a low toxicity profile, and has minimum side effects. Ferulic acid exhibits various therapeutic actions by modulation of various signal transduction pathways such as Nrf2, p38, and mTOR. The actions exhibited by ferulic acid include anti-apoptosis, antioxidant, anti-inflammatory, antidiabetic, anticarcinogenic, hepatoprotection, cardioprotection, activation of transcriptional factors, expression of genes, regulation of enzyme activity, and neuroprotection, which further help in treating various pathophysiological conditions such as cancer, skin diseases, brain disorders, diabetes, Parkinson's disease, Alzheimer's disease, hypoxia, hepatic disorders, H1N1 flu, and viral infections. The current review focuses on the significance of natural products as sources of multitarget compounds, and a primary focus has been made on ferulic acid and its mechanism, role, and protective action in various ailments.

Structure-based drug design of peroxisome proliferator-activated receptor gamma inhibitors: ferulic acid and derivatives.

Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ), ligand-activated transcription factor, is a key modulator of genes considered in diabetes development as well as treatment. Adipogenesis di...

Effects of ferulic acid on muscle development and intestinal microbiota of zebrafish

Abstract: Ferulic acid (FA) is one of a common ingredients in Chinese herbal medicine. FA has the interesting property of promoting growth and improving meat quality in livestock, but the mechanism is not understood. This study evaluated both safety and mechanism of efficacy in zebrafish model. At 15 μg/mL or above, FA led to pericardial oedema and delayed growth in zebrafish embryos. Dietary FA promoted growth and feed assimilation in male adult zebrafish. Genes related to myogenic development (myod1, myog and myf5) were significantly upregulated by FA and muscle fibre width in skeletal muscle was increased. At 20 µg/g, FA significantly increased number of goblet cells in zebrafish intestinal tissue, and gut microbiota composition also changed. Based on 16s rRNA gene sequences, 20 μg/g FA decreased Firmicutes and increased Bacteroides. 20 μg/g FA also stimulated the expression of PPAR-α, a gene associated with fat metabolism, and decreased the expression of PPAR-β and PPAR-γ. These gene expression changes were beneficial to fatty acid synthesis and metabolism and decreased fat deposition. Our overall results indicated that FA can be a safe growth promotor in fish particularly in skeletal muscles.