Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects on
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 (IC
) values of 0.26⁻1.02 µM), nitrite accumulation (IC
values of 2.4⁻7.0 µM), and cyclooxygenase-2 (COX-2) activity (IC
values of 11.74⁻24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with IC
values of 3.77⁻5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with IC
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.
In this study, atomic level interactions of 1:1 Choline Chloride (ChCl): Acetylsalicylic Acid (ASA) therapeutic deep eutectic solvent (THDES) has been investigated by combining the molecular dynamics ...(MD), density functional theory (DFT) and spectroscopic (Raman and IR) techniques. Atom-atom radial distribution functions (RDFs) based on MD simulation reveal that hydrogen bonds are formed between Cl-…HOCh+ and Cl-…HOCOOH of the THDES, where Cl- works as a bridge between ASA and Ch+. Cation-anion electrostatic attractions are disrupted by highly interconnected hydrogen bonds. Cluster conformers of the THDES are isolated from MD simulation and optimized using ωB97XD/6-311++G (d,p) level of theory, in which the strongest H-bonds are found among OHCh+…Cl- (2.37 Å) and Cl-…HOCOOH (2.40 Å). Charge transfer calculations, using CHEPLG and NBO analysis, disclose that the charge of Cl- is reduced in the cluster structures and transferred to Ch+ and ASA. Further analyses are conducted using experimental and computed spectroscopic data. These confirm the formation of the THDES as peaks for -COOH, -COOR, and -OH functional groups of ASA and ChCl are either get broadened or disappeared in the spectra of the cluster conformers. Moreover, principal component analysis (PCA) assists to understand the feature of the simulated data and confirms the formation of the THDES. Solvent selectivity triangle (SST) of solvatochromic parameters also demonstrate that this THDES have some important properties similar to ionic liquids and common deep eutectic solvent.
SARS-CoV-2 membrane (M) protein performs a variety of critical functions in virus infection cycle. However, the expression and purification of membrane protein structure is difficult despite ...tremendous progress. In this study, the 3 D structure is modeled followed by intensive validation and molecular dynamics simulation. The lack of suitable homologous templates (>30% sequence identities) leads us to construct the membrane protein models using template-free modeling (de novo or ab initio) approach with Robetta and trRosetta servers. Comparing with other model structures, it is evident that trRosetta (TM-score: 0.64; TM region RMSD: 2 Å) can provide the best model than Robetta (TM-score: 0.61; TM region RMSD: 3.3 Å) and I-TASSER (TM-score: 0.45; TM region RMSD: 6.5 Å). 100 ns molecular dynamics simulations are performed on the model structures by incorporating membrane environment. Moreover, secondary structure elements and principal component analysis (PCA) have also been performed on MD simulation data. Finally, trRosetta model is utilized for interpretation and visualization of interacting residues during protein-protein interactions. The common interacting residues including Phe103, Arg107, Met109, Trp110, Arg131, and Glu135 in the C-terminal domain of M protein are identified in membrane-spike and membrane-nucleocapsid protein complexes. The active site residues are also predicted for potential drug and peptide binding. Overall, this study might be helpful to design drugs and peptides against the modeled membrane protein of SARS-CoV-2 to accelerate further investigation.
Communicated by Ramaswamy H. Sarma
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.
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.
Over 50 peptides, which were known to inhibit SARS-CoV-1, were computationally screened against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. Based on the binding affinity and ...interaction, 15 peptides were selected, which showed higher affinity compared to the α-helix of the human ACE2 receptor. Molecular dynamics simulation demonstrated that two peptides, S2P25 and S2P26, were the most promising candidates, which could potentially block the entry of SARS-CoV-2. Tyr489 and Tyr505 residues present in the “finger-like” projections of the RBD were found to be critical for peptide interaction. Hydrogen bonding and hydrophobic interactions played important roles in prompting peptide–protein binding and interaction. Structure–activity relationship indicated that peptides containing aromatic (Tyr and Phe), nonpolar (Pro, Gly, Leu, and Ala), and polar (Asn, Gln, and Cys) residues were the most significant contributors. These findings can facilitate the rational design of selective peptide inhibitors targeting the spike protein of SARS-CoV-2.
Rationale
Calf‐thymus (CT‐DNA) is widely used as a binding agent. The commercial samples are known to be “highly polymerized DNA” samples. CT‐DNA is known to be fragile in particular upon ultrasonic ...wave irradiation. Degradation products could have dramatic consequences on its bio‐sensing activity, and an accurate determination of the molecular weight distribution and stability of commercial samples is highly demanded.
Methods
We investigated the sensitivity of charge detection mass spectrometry (CDMS), a single‐molecule MS method, both with single‐pass and ion trap CDMS (“Benner” trap) modes to the determination of the composition and stability (under multiphoton IR irradiation) of calf‐thymus DNAs. We also investigated the changes in molecular weight distributions in the course of sonication by irradiating ultrasonic waves to CT‐DNA.
Results
We report, for the first time, the direct molecular weight (MW) distribution of DNA sodium salt from calf‐thymus revealing two populations at high (~10 MDa) and low (~3 MDa) molecular weights. We evidence a transition between the high‐MW to the low‐MW distribution, confirming that the low‐MW distribution results from degradation of CT‐DNA. Finally, we report also IRMPD experiments carried out on trapped single‐stranded linear DNAs from calf‐thymus allowing extraction of their activation energy for unimolecular dissociation.
Conclusions
We show that single‐pass CDMS is a direct, efficient and accurate MS‐based approach to determine the composition of calf‐thymus DNAs. Furthermore, ion trap CDMS allows us to evaluate the stability (both under multiphoton IR irradiation and in the course of sonication by irradiating ultrasonic wave) of calf‐thymus DNAs.
In the design of greener chemicals, deep eutectic solvents (DESs) are considered as one of the most versatile alternative media with widespread applications. DESs have the advantages of being ...nonflammable with negligible vapor pressure compared to the traditional solvents. They share many characteristics of ionic liquids, but DESs are cheaper to formulate, typically nontoxic, highly pure, recyclable, biodegradable, and are suitable for use with biological systems. In this article, the two emerging and unconventional types of DESs, therapeutic DES (THEDES) and amino acid-based DES (AADES) are reviewed. Based on the published literature, choline chloride and menthol are the two most common constituents to formulate THEDESs, while proline is the most common component to formulate AADESs. THEDESs have primarily been developed to enhance the efficacy of drugs, whereas AADESs have been explored for pharmaceuticals as well as for the extraction of phytochemicals, radioactive iodine capture, oil separation from ores, and to synthesize bioactive compounds. Since detailed knowledge of their structures, nonbonding interactions, formulations, and applications are yet to be explored, the aim of this review is to compile these details and provide a solid background for the future research.
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•Two unconventional and emerging deep eutectic solvents•Therapeutic deep eutectic solvent (THDES) and amino acid-based deep eutectic solvent (AADES)•Formulation, molar ratios, structural insights, and applications•THDES are mainly developed for pharmaceuticals•AADES have been explored for pharmaceuticals, for the extraction of value-added compounds, and as media for green synthesis.
A series of halogen-directed donepezil drugs has been designed to inhibit acetyl cholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize the chair as well as boat ...conformers of the parent drug and modified ligands at B3LYP/MidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment, enthalpy, free energy and molecular orbitals of these ligands are also investigated to understand how the halogen-directed modifications impact the ligand structure and govern the non-bonding interactions with the receptors. Molecular docking calculation has been performed to understand the similarities and differences between the binding modes of unmodified and halogenated chair-formed ligands. Molecular docking indicated donepezil and modified ligands had non-covalent interactions with hydrophobic gorges and anionic subsites of AChE. The –CF
3
-directed ligand possessed the most negative binding affinity. Non-covalent interactions within the ligand–receptor systems were found to be mostly hydrophobic and π- stacking type. F, Cl and –CF
3
containing ligands emerge as effective and selective AChE inhibitors, which can strongly interact with the two active sites of AChE. In addition, we have also investigated selected pharmacokinetic parameters of the parent and modified ligands.
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.
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