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Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects on Caenorhabditis elegans through inactivation of the oncogenic kinase, p21-activated kinase 1 (PAK1). Herein, five prenylated flavonoids from OP, nymphaeol-A (NA), nymphaeol-B (NB), nymphaeol-C (NC), isonymphaeol-B (INB), and 3′-geranyl-naringenin (GN), were evaluated for their anti-inflammatory, anti-diabetic, and anti-Alzheimer’s effects using in vitro techniques. They showed significant anti-inflammatory effects through inhibition of albumin denaturation (half maximal inhibitory concentration (IC50) values of 0.26–1.02 µM), nitrite accumulation (IC50 values of 2.4–7.0 µM), and cyclooxygenase-2 (COX-2) activity (IC50 values of 11.74–24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with IC50 values of 3.77–5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with IC50 values of 7.23 and 7.77 µM, respectively. Molecular docking results indicated that OP compounds have good binding affinity to the α-glucosidase and acetylcholinesterase proteins, making non-bonded interactions with their active residues and surrounding allosteric residues. In addition, none of the compounds violated Lipinski’s rule of five and showed notable toxicity parameters. Density functional theory (DFT)-based global reactivity descriptors demonstrated their high reactive nature along with the kinetic stability. In conclusion, this combined study suggests that OP components might be beneficial in the treatment of inflammation, type 2 diabetes mellitus, and Alzheimer’s disease.

Serine-threonine kinase11 (STK11) is a tumor suppressor gene which plays a key role in regulating cell growth and apoptosis. It is widely known as a multitasking kinase and engaged in cell polarity, cell cycle arrest, chromatin remodeling, energy metabolism, and Wnt signaling. The substitutions of single amino acids in highly conserved regions of the STK11 protein are associated with Peutz–Jeghers syndrome (PJS), which is an autosomal dominant inherited disorder. The abnormal function of the STK11 protein is still not well understood. In this study, we classified disease susceptible single nucleotide polymorphisms (SNPs) in STK11 by using different computational algorithms. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking and molecular dynamics analysis. Our results show that W239R and W308C variants are likely to be highly deleterious mutations found in the catalytic kinase domain, which may destabilize structure and disrupt the activation of the STK11 protein as well as reduce its catalytic efficiency. The W239R mutant is likely to have a greater impact on destabilizing the protein structure compared to the W308C mutant. In conclusion, these mutants can help to further realize the large pool of disease susceptibilities linked with catalytic kinase domain activation of STK11 and assist to develop an effective drug for associated diseases.

Among neurodegenerative disorders, Alzheimer's disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank and MD simulation. In addition, it is observed that the π- π stacking with the residues of Trp86, Tyr337, Tyr341, Tyr124 and Trp286 may be required for strong ligand binding. Moreover, ADME/T analysis suggests that modified derivatives are less toxic and have improved pharmacokinetic properties than those of the parent drug. These results further confirm the ability of metal-directed drugs to bind simultaneously to the active sites of AChE and support them as potential candidates for the future treatment of Alzheimer's disease.

Objective Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women. Toll-like receptor 5 (TLR5), an autoimmune signaling receptor that plays a role in cancer, can be exploited for the suppression of human colon cancer. Salmonella flagellin protein, a novel agonist of TLR5 activating downstream signaling, could be a basis for designing anticancer peptides. Methods The three-dimensional crystal structure of TLR5 (PDB ID: 3J0A, Resolution = 26.0 Å) was optimized using the AMBER force field in the YASARA suit. In silico enzymatic digestion tool, PeptideCutter, was used to identify peptides from Salmonella flagellin, an agonist against human TLR5. The 3D structure of the peptides was generated using PEP-FOLD3. These peptides were screened against human TLR5 using shape complementarity principles based on the binding affinity and interactions with the active residue of TLR5 monomer, and the selected peptides were further validated by molecular dynamic (MD) simulation. Results In this study, we generated 42 peptides from Salmonella flagellin protein by in silico protein digestion. Then, based on a new hidden Markov model sub-optimal conformation sampling approach as well as the size of the fragments, we select 38 effective peptides from these 42 cleavages. These peptides were screened against the monomeric Xray structure of human TLR5 using shape complementarity principles. Based on the binding affinity and interactions with the active residue of TLR5 monomer (residues 294 and 366 of TLR5), nine top-scored peptides were selected for the initial molecular dynamic (MD) simulation. Among these peptides, Clv10, Clv17, and Clv28 showed high stability and less flexibility during MD simulation. A 1 μs MD simulation was performed on TLR5-Clv10, TLR-Clv17, and TLR5-Clv28 complexes to further analyze the stability, conformational changes, and binding mode (Clv10, Clv17, and Clv28). During this MD study, the peptides showed high salt bridges and ionic interactions with residue ASP294 and residue ASP366 throughout the simulation and remained in the concave of the human TLR5 monomer. The RMSD and Rg values showed that the peptide-protein complexes become stable after 200 ns of contraction and extraction. Conclusion These findings can facilitate the rational design of selected peptides as an agonist of TLR5, which have antitumor activity, suppress colorectal cancer tumors, and can be used as promising candidates and novel agonists of TLR5. Graphical Abstract

A new dimeric prenylated quinolone alkaloid, named 2,11-didemethoxy-vepridimerine A, was isolated from the root bark of Zanthoxylum rhetsa, together with twelve known compounds. The structure of the new compound was elucidated on the basis of spectroscopic investigations (NMR and Mass). The interaction of the isolated compounds with the main protease of SARS-CoV-2 (Mpro) was evaluated using molecular docking followed by MD simulations. The result suggests that 2,11-didemethoxy-vepridimerine A, the new compound, has the highest negative binding affinity against the Mpro with a free energy of binding of −8.5 Kcal/mol, indicating interaction with the Mpro. This interaction was further validated by 100 ns MD simulation. This implies that the isolated new compound, which can be employed as a lead compound for an Mpro-targeting drug discovery program, may be able to block the action of Mpro.

Sea cucumbers have long been utilized in foods and Asiatic folk medicines for their nutritive and health benefits. Herein, three sea cucumber species were investigated and Holothuria atra showed the highest cytotoxicity among these. Next, a desulfated saponin, desulfated echinoside B (DEB), was purified from H. atra through bioassay-guided fractionation. LC-ESI-MS (Liquid chromatography-electrospray ionization mass spectrometry) analysis also showed H. atra to be a rich source of saponins. DEB showed cytotoxicity on cancer cells with IC50 values of 0.5–2.5 µM, and on brine shrimps with an IC50 value of 9.2 µM. In molecular docking studies, DEB was found to bind strongly with the catalytic domain of PAK1 (p21-activated kinase 1) and it showed binding energy of −8.2 kcal/mol compared to binding energy of −7.7 kcal/mol for frondoside A (FRA). Both of them bind to the novel allosteric site close to the ATP-binding cleft. Molecular dynamics (MD) simulation demonstrated that DEB can form a more stable complex with PAK1, remaining inside the allosteric binding pocket and forming the maximum number of hydrogen bonds with the surrounding residues. Moreover, important ligand binding residues were found to be less fluctuating in the DEB-PAK1 complex than in the FRA-PAK1 complex throughout MD simulation. Our experimental and computational studies showed that both DEB and FRA can act as natural allosteric PAK1 inhibitors and DEB appeared to be more promising than FRA.

Mass spectrometry-based methods have made significant progress in characterizing post-translational modifications in peptides and proteins; however, certain aspects regarding fragmentation methods must still be improved. A good technique is expected to provide excellent sequence information, locate PTM sites, and retain the labile PTM groups. To address these issues, we investigate 10.6 μm IRMPD, 213 nm UVPD, and combined UV and IR photodissociation, known as HiLoPD (high-low photodissociation), for phospho-, sulfo-, and glyco-peptide cations. IRMPD shows excellent backbone fragmentation and produces equal numbers of N- and C-terminal ions. The results reveal that 213 nm UVPD and HiLoPD methods can provide diverse backbone fragmentation producing a/x, b/y, and c/z ions with excellent sequence coverage, locate PTM sites, and offer reasonable retention efficiency for phospho- and glyco-peptides. Excellent sequence coverage is achieved for sulfo-peptides and the position of the SO 3 group can be pinpointed; however, widespread SO 3 losses are detected irrespective of the methods used herein. Based on the overall performance achieved, we believe that 213 nm UVPD and HiLoPD can serve as alternative options to collision activation and electron transfer dissociations for phospho- and glyco-proteomics. Graphical Abstract ᅟ

Dengue, a mosquito-borne disease, has appeared as a major infectious disease globally. The virus requires its proteins to replicate and reproduce in the host cell. The NS3 protease converts the polyprotein to functional proteins with the help of the NS2B cofactor. Thus, NS3 protease is a promising target to develop antiviral inhibitors against the dengue virus. A systematic screening including ADMET properties, molecular docking, molecular dynamics (MD) simulation, binding free energy calculation, and QSAR studies is carried out to predict potent inhibitors against the NS3 protease. From the screening of 40 antiviral phytochemicals, ADMET properties analysis was used to screen out ligands that violate ADME rules and have probable toxicity. Cyanidin 3-Glucoside, Dithymoquinone, and Glabridin were predicted to be potent inhibitors against the NS3 protease according to their binding affinity. These ligands showed several noncovalent interactions, including hydrogen bond, hydrophobic interaction, electrostatic interaction, pi-sulfur interactions. The ligand-protein complexes were further scrutinized using 250 ns molecular dynamics simulation. The MM-PBSA binding free energy calculation was conducted to investigate their binding stability in dynamic conditions. The calculated pIC50(mM) value was predicted using the QSAR model with 89.91% goodness of fit. The predicted biologocal activity value for the ligands indicates they might have good potency. [Display omitted] •40 Antiviral phytochemicals screened against DENV-2 NS3-NS2B protease.•Initially, ADMET and Molecular docking were performed for screening.•250ns MD and MM/PBSA were implemented for the three selected candidates.•Phytochemicals Glabridin altered the protein-cofactor protein interactions interface.•QSAR model were studied for in-silico activity prediction.

Herein we report the successful implementation of the consecutive and simultaneous photodissociation with high (213 nm) and low (10.6 μm) energy photons (HiLoPD, high-low photodissociation) on ubiquitin in a quadrupole-Orbitrap mass spectrometer. Absorption of high-energy UV photon is dispersed over the whole protein and stimulates extensive C–C α backbone fragmentation, whereas low-energy IR photon gradually increases the internal energy and thus preferentially dissociates the most labile amide (C–N) bonds. We noticed that simultaneous irradiation of UV and IR lasers on intact ubiquitin in a single MS/MS experiment provides a rich and well-balanced fragmentation array of a/x, b/y, and z ions. Moreover, secondary fragmentation from a/x and z ions leads to the formation of satellite side-chain ions (d, v, and w) and can help to distinguish isomeric residues in a protein. Implementation of high-low photodissociation in a high-resolution mass spectrometer may offer considerable benefits to promote a comprehensive portrait of protein characterization. Graphical Abstract ᅟ

The receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein plays a vital role in binding and internalization through the alpha-helix (AH) of human angiotensin-converting enzyme 2 (hACE2). Thus, it is a potential target for designing and developing antiviral agents. Inhibition of RBD activity of the S protein may be achieved by blocking RBD interaction with hACE2. In this context, inhibitors with large contact surface area are preferable as they can form a potentially stable complex with RBD of S protein and would not allow RBD to come in contact with hACE2. Peptides represent excellent features as potential anti-RBD agents due to better efficacy, safety, and tolerability in humans compared to that of small molecules. The present study has selected 645 antiviral peptides known to inhibit various viruses and computationally screened them against the RBD of SARS-CoV-2 S protein. In primary screening, 27 out of 645 peptides exhibited higher affinity for the RBD of S protein compared to that of AH of the hACE2 receptor. Subsequently, AVP1795 appeared as the most promising candidate that could inhibit hACE2 recognition by SARS-CoV 2 as was predicted by the molecular dynamics simulation. The critical residues in RBD found for protein-peptide interactions are TYR 489, GLY 485, TYR 505, and GLU 484. Peptide-protein interactions were substantially influenced by hydrogen bonding and hydrophobic interactions. This comprehensive computational screening may provide a guideline to design the most effective peptides targeting the spike protein, which could be studied further in vitro and in vivo for assessing their anti-SARS CoV-2 activity. [Display omitted] •Antiviral peptides can be a promising therapeutic strategy to inhibit SARS-CoV-2.•645 antiviral peptides were screened against RBD of the spike protein of SARS-CoV-2.•150 ns molecular dynamics simulation has been performed for peptide-protein complexes.•Two promising peptides were found which show significant binding and interactions with RBD of SARS CoV-2.