• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2291-2295
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• 2016

Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verber's filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study.

• Molecules and Cells
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• v.28 no.5
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• pp.447-453
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• 2009

The quorum sensing (QS) inhibitors that antagonize TraR, a receptor protein for N-3-oxo-octanoyl-L-homoserine lactones (3-oxo-C8-HSL), a QS signal of Agrobacterium tumefaciens were developed. The structural analogues of 3-oxo-C8-HSL were designed by in silico molecular modeling using SYBYL packages, and synthesized by the solid phase organic synthesis (SPOS) method, where the carboxamide bond of 3-oxo-C8-HSL was replaced with a nicotinamide or a sulfonamide bond to make derivatives of N-nicotinyl-L-homoserine lactones or N-sulfonyl-L-homoserine lactones. The in vivo inhibitory activities of these compounds against QS signaling were assayed using reporter systems and compared with the estimated binding energies from the modeling study. This comparison showed fairly good correlation, suggesting that the in silico interpretation of ligand-receptor structures can be a valuable tool for the pre-design of better competitive inhibitors. In addition, these inhibitors also showed anti-biofilm activities against Pseudomonas aeruginosa.

• Genomics & Informatics
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• v.12 no.4
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• pp.276-282
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• 2014

The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug-resistant MTB clinical strains are showing resistance to isoniazid and rifampicin (RIF), the frontline anti-tuberculosis drugs. Mutation in rpoB, the beta subunit of DNA-directed RNA polymerase of MTB, is reported to be a major cause of RIF resistance. Amongst mutations in the well-defined 81-base-pair central region of the rpoB gene, mutation at codon 450 (S450L) and 445 (H445Y) is mainly associated with RIF resistance. In this study, we modeled two resistant mutants of rpoB (S450L and H445Y) using Modeller9v10 and performed a docking analysis with RIF using AutoDock4.2 and compared the docking results of these mutants with the wild-type rpoB. The docking results revealed that RIF more effectively inhibited the wild-type rpoB with low binding energy than rpoB mutants. The rpoB mutants interacted with RIF with positive binding energy, revealing the incapableness of RIF inhibition and thus showing resistance. Subsequently, this was verified by molecular dynamics simulations. This in silico evidence may help us understand RIF resistance in rpoB mutant strains.

• Food Science of Animal Resources
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• v.43 no.1
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• pp.184-194
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• 2023

Recently, interest in food-derived bioactive peptides as promising ingredients for the prevention and improvement of hypertension is increasing. The purpose of this study was to determine the structure and antihypertensive effect of an antioxidant peptide purified from velvet antler in a previous study and evaluate its potential as a various bioactive peptide. Molecular weight (MW) and amino acid sequences of the purified peptide were determined by quadrupole time-of-flight electrospray ionization mass spectroscopy. The angiotensin I-converting enzyme (ACE) inhibition activity of the purified peptide was assessed by enzyme reaction methods and in silico molecular docking analysis to determine the interaction between the purified peptide and ACE. Also, antihypertensive effect of the purified peptide in spontaneously hypertensive rats (SHRs) was investigated. The purified antioxidant peptide was identified to be a pentapeptide Asp-Asn-Arg-Tyr-Tyr with a MW of 730.31 Da. This pentapeptide showed potent inhibition activity against ACE (IC₅₀ value, 3.72 μM). Molecular docking studies revealed a good and stable binding affinity between purified peptide and ACE and indicated that the purified peptide could interact with HOH2570, ARG522, ARG124, GLU143, HIS387, TRP357, and GLU403 residues of ACE. Furthermore, oral administration of the pentapeptide significantly reduced blood pressure in SHRs. The pentapeptide derived from enzymatic hydrolysate of velvet antler is an excellent ACE inhibitor. It might be effectively applied as an animal-based functional food ingredient.

• Bulletin of the Korean Chemical Society
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• v.28 no.6
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• pp.941-946
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• 2007

Bacillus halodurans O-methyltransferase (BhOMT) is a S-adenosylmethionine (SAM or AdoMet) dependent methyltransferase. Three dimensional structure of the BhOMT bound to S-adenosyl-L-homocysteine (SAH or AdoHcy) has been determined by comparative homology modeling. BhOMT has 40% sequence identity with caffeoyl-CoA 3-O-methyltransferase (CCoAOMT) from alfalfa. Based on x-ray structure of CCoAOMT, three dimensional structure of BhOMT was determined using MODELLER. The substrate binding sites of these two proteins showed slight differences, but these differences were important to characterize the substrate of BhOMT. Automated docking study showed that four flavonoids, quercetin, fisetin, myricetin, and luteolin which have two hydroxyl groups simultaneously at 3'- and 4'-position in the B-ring and structural rigidity of Cring resulting from the double bond characters between C2 and C3, were well docked as ligands of BhOMT. These flavonoids form stable hydrogen bondings with K211, R170, and hydroxyl group at 3'-position in the Bring has stable electrostatic interaction with Ca2+ ion in BhOMT. This study will be helpful to understand the biochemical function of BhOMT as an O-methyltransferase for flavonoids.

• Biomolecules & Therapeutics
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• v.30 no.5
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• pp.427-434
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• 2022

The drug repurposing strategy has been applied to the development of emergency COVID-19 therapeutic medicines. Current drug repurposing approaches have been directed against RNA polymerases and viral proteases. Recently, we found that the inhibition of the interaction between the SARS-CoV-2 structural nucleocapsid (N) and spike (S) proteins decreased viral replication. In this study, drug repurposing candidates were screened by in silico molecular docking simulation with the SARS-CoV-2 structural N protein. In the ChEMBL database, 1994 FDA-approved drugs were selected for the in silico virtual screening against the N terminal domain (NTD) of the SARS-CoV-2 N protein. The tyrosine 109 residue in the NTD of the N protein was used as the center of the ligand binding grid for the docking simulation. In plaque forming assays performed with SARS-CoV-2 infected Vero E6 cells, atovaquone, abiraterone acetate, and digoxin exhibited a tendency to reduce the size of the viral plagues without affecting the plaque numbers. Abiraterone acetate significantly decreased the accumulation of viral particles in the cell culture supernatants in a concentration-dependent manner. In addition, abiraterone acetate significantly decreased the production of N protein and S protein in the SARS-CoV-2-infected Vero E6 cells. In conclusion, abiraterone acetate has therapeutic potential to inhibit the viral replication of SARS-CoV-2.

• Genomics & Informatics
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• v.21 no.3
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• pp.43.1-43.13
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• 2023

Melanin is synthesized by tyrosinase to protect the skin from ultraviolet light. However, overproduction and accumulation of melanin can result in hyperpigmentation and skin melanoma. Tyrosinase inhibitors are commonly used in the treatment of hyperpigmentation. Natural tyrosinase inhibitors are often favoured over synthetic ones due to the potential side effects of the latter, which can include skin irritation, allergies, and other adverse reactions. Nuciferine, an alkaloid derived from Nelumbo nucifera, exhibits potent antioxidant and anti-proliferative properties. This study focused on the in silico screening of nuciferine for anti-tyrosinase activity, using kojic acid, ascorbic acid, and resorcinol as standards. The tyrosinase protein target was selected through homology modeling. The residues of the substrate binding pocket and active site pockets were identified for the purposes of grid box optimization and docking. Therefore, nuciferine is a potent natural tyrosinase inhibitor and shows promising potential for application in the treatment of hyperpigmentation and skin melanoma.

• Journal of Microbiology and Biotechnology
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• v.26 no.11
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• pp.1845-1854
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• 2016

The transglycosylation activity of amylosucrase (ASase) has received significant attention owing to its use of an inexpensive donor, sucrose, and broad acceptor specificity, including glycone and aglycone compounds. The transglycosylation reaction of recombinant ASase from Deinococcus radiopugnans (DRpAS) was investigated using various phenolic compounds, and quercetin-3-O-rutinoside (rutin) was found to be the most suitable acceptor molecule used by DRpAS. Two amino acid residues in DRpAS variants (DRpAS Q299K and DRpAS Q299R), assumed to be involved in acceptor binding, were constructed by site-directed mutagenesis. Intriguingly, DRpAS Q299K and DRpAS Q299R produced 10-fold and 4-fold higher levels of rutin transglycosylation product than did the wild-type (WT) DRpAS, respectively. According to in silico molecular docking analysis, the lysine residue at position 299 in the mutants enables rutin to more easily position inside the active pocket of the mutant enzyme than in that of the WT, due to conformational changes in loop 4.

• Journal of Microbiology and Biotechnology
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• v.28 no.8
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• pp.1401-1411
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• 2018

The serine-threonine kinase AKT plays a pivotal role in tumor progression and is frequently overactivated in cancer cells; this protein is therefore a critical therapeutic target for cancer intervention. We aimed to identify small molecule inhibitors of the pleckstrin homology (PH) domain of AKT to disrupt binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby downregulating AKT activity. Liposome pulldown assays coupled with fluorescence spectrometry were used to screen flavonoids for inhibition of the AKT PH-PIP3 interaction. Western blotting was used to determine the effects of the inhibitors on AKT activation in cancer cells, and in silico docking was used for structural analysis and optimization of inhibitor structure. Several flavonoids showing up to 50% inhibition of the AKT PH-PIP3 interaction decreased the level of AKT activation at the cellular level. In addition, the modified flavonoid showed increased inhibitory effects and the approach would be applied to develop anticancer drug candidates. In this study, we provide a rationale for targeting the lipid-binding domain of AKT, rather than the catalytic kinase domain, in anticancer drug development.

• Genomics & Informatics
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• v.19 no.1
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• pp.7.1-7.13
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• 2021

Levodopa (L-DOPA) therapy is normally practised to treat motor pattern associated with Parkinson disease (PD). Additionally, several inhibitory drugs such as Entacapone and Opicapone are also cosupplemented to protect peripheral inactivation of exogenous L-DOPA (~80%) that occurs due to metabolic activity of the enzyme catechol-O-methyltransferase (COMT). Although, both Entacapone and Opicapone have U.S. Food and Drug Administration approval but regular use of these drugs is associated with high risk of side effects. Thus, authors have focused on in silico discovery of phytochemicals and evaluation of their effectiveness against human soluble COMT using virtual screening, molecular docking, drug-like property prediction, generation of pharmacophoric property, and molecular dynamics simulation. Overall, study proposed, nine phytochemicals (withaphysalin D, withaphysalin N, withaferin A, withacnistin, withaphysalin C, withaphysalin O, withanolide B, withasomnine, and withaphysalin F) of plant Withania somnifera have strong binding efficiency against human COMT in comparison to both of the drugs i.e., Opicapone and Entacapone, thus may be used as putative bioenhancer in L-DOPA therapy. The present study needs further experimental validation to be used as an adjuvant in PD treatment.