Affinity Of Complex Research Articles

Live-cell FRET assay on the stoichiometry and affinity of the YAP complexes in MCF-7 cells

Live-cell FRET assay on the stoichiometry and affinity of the YAP complexes in MCF-7 cells

Is Silver a Precious Metal for G-Quadruplex Stabilization Mediated by Porphyrins?

Cancer is a leading cause of death, so continuous efforts into cancer therapy are imperative. In tumor cells, telomerase and oncogene activity are key points for uncontrolled cell growth. Targeting these processes with ligands that inhibit telomerase and/or reduce oncogene expression has been identified as a promising cancer therapy. This study evaluated the selectivity and affinity of the silverII complex of 5,10,15,20-tetrakis(N-methyl-4-pyridinium)porphyrin (AgTMPyP) to stabilize DNA sequences capable of forming G4 structures mimicking the telomeric and oncogene regions, using spectroscopic, biochemical methods and in vitro assays. The tetracationic silver complex was compared with the free base, H2TMPyP, and the zincII complex, ZnTMPyP. The results obtained from UV-Vis and fluorescence methods pointed to a great affinity and good selectivity of AgTMPyP to G4 structures, especially for the oncogene MYC. In general, an increase in the ability of the studied ligands for 1O2 generation when interacting with oncogenic and telomeric G4 sequences was found. The results of the PCR stop assays proved that AgTMPyP has the ability to inhibit Taq polymerase. Additionally, in vitro assays demonstrated that the silverII complex exhibits low cytotoxicity against HaCaT- an immortalized, non-tumorigenic, skin keratinocytes cell line-and, although nonexclusive, AgTMPyP shows nuclear co-localization.

SG-ML-PLAP: A structure-guided machine learning-based scoring function for protein-ligand binding affinity prediction.

Computational methods to predict binding affinity of protein-ligand complex have been used extensively to design inhibitors for proteins selected as drug targets. In recent years machine learning (ML) is being increasingly used for design of drugs/inhibitors. However, ranking compounds as per their experimental binding affinity has remained a major challenge. Therefore, it is necessary to develop ML-based scoring function (MLSF) for predicting the binding affinity of protein-ligand complexes. In this work, protein-ligand interaction features, namely, extended connectivity interaction fingerprints (ECIF), derived from the PDBbind dataset have been used to build ML models for binding affinity prediction. The benchmarking has been done on the Comparative Assessment of Scoring Functions (CASF) dataset and also by predicting the binding affinity of unseen protein-ligand complexes which have structural features different from those present in the training dataset. Furthermore, an improvement in the performance of MLSF on the redocked CASF complexes generated by AutoDock Vina software was seen when the training set consisting of crystal structures was supplemented with redocked protein-ligand complexes. The MLSF trained on crystal structures alone using a combination of ECIF and VINA features also predicted binding affinities of crystal as well as docked complexes with high accuracy. Overall, the MLSF developed in this work shows improved performance compared to conventional SFs and several other MLSFs. It will be a valuable resource for identifying novel inhibitors by structure-based virtual screening protocols. The proposed MLSF SG-ML-PLAP (Structure-Guided Machine-Learning-based Protein-Ligand Affinity Predictor) is freely accessible as a webserver, http://www.nii.ac.in/sg-ml-plap.html.

An Ion Pair Receptor for Selective Solid-Liquid Extraction of LiCl.

We have synthesized a new ion pair receptor (2) consisting of a cone-calix[4]arene bearing a combination of ethyl esters and ethers as a cation binding site and a calix[4]pyrrole subunit acting as an anion binding site. Ion pair receptor 2 complexes LiCl, NaCl, and CsCl among alkali metal chloride salts with distinct complexation modes and affinities in 10 % methanol-d4 in chloroform-d. For instance, relatively small Li+ and Na+ cations are bound to the oxygen atoms of the functionalized calix[4]arene lower rim with Cl- being hydrogen bonded to the calix[4]pyrrole NHs while the larger Cs+ cation is bound to the cone-shaped calix[4]pyrrole cavity via a π-cation interaction. By contrast, in the co-presence of all MCl salts (M=Li, Na, K, Rb, and Cs), receptor 2 binds LiCl with complete selectivity. Besides, receptor 2 is capable of extracting LiCl selectively into a chloroform or a dichloromethane organic phase from its solid source containing all other MCl salts.

Synthesis, antimicrobial, antioxidant, tyrosinase inhibitory activities, and computational studies of novel chromen[2,3-c]pyrazole derivatives.

In this study, one-pot multicomponent reactions of novel chromeno[2,3-c]pyrazole derivatives (1-14) were performed using an AlCl3 catalyst via cyclisation. Various spectral and chromatographic techniques were used to elucidate the structure of the synthesised derivatives (1-14). The synthesised compounds were then inspected for their antibacterial, antioxidant, and tyrosinase inhibition activities. An in silico screening approach was also employed to identify highly potent derivatives. Besides, we utilised density functional theory (DFT) with the B3LYP/6-31G+ (d, p) basis set to optimise the newly modified derivatives. This approach was used to calculate various properties, including electron density, electrostatic potential map, interaction strength, frontier molecular orbital energy, and reactivity characteristics. To examine the binding affinity, modes, and stability of the protein-drug complex, molecular docking with the 2Y9X protein structure were employed. The findings from DFT computations, along with physicochemical information and molecular docking binding affinity, showed promising results than standard and low active compound 1. The absorption, metabolism, and cytotoxic characteristics of all the novel derivatives were investigated in the ADMET prediction. Our findings could prove valuable in developing novel drugs for medicinal and pharmaceutical fields.

K‐wise multi‐graph matching

AbstractMulti‐graph matching (MGM), which aims to find correspondences among multiple graphs, is an extension of conventional two‐graph matching. Existing MGM methods fall into two categories: pairwise based and tensor based. Pairwise‐based methods consider similarities between every two features; while tensor‐based methods consider the overall similarity among all features, offering much more flexibility similarity measurements and less information loss, but at the cost of exorbitant computational demands. Here, a fresh perspective on MGM task is delivered, that is, matching based on any k features. It enables the consideration of more complex affinity relationship beyond pairwise while keeping computational demands within a manageable threshold. Furthermore, a factorization technique for the k‐wise global affinity matrix is proposed, significantly reducing space complexity. This approach unifies existing MGM methods and inspires future research focusing on k‐wise affinity relationship, showcasing both theoretical and practical advancements in the field. Experiments on synthetic and real‐world datasets demonstrate the superiority of our method.

Synthesis, Urease Inhibitory Activity, Molecular Docking, Dynamics, MMGBSA and DFT Studies of Hydrazone-Schiff Bases Bearing Benzimidazole Scaffold.

In this study, eleven hydrazone-Schiff bases bearing benzimidazole moiety were synthesized successfully via three step reactions and structures of these products were deduced by HR-ESI-MS, 1H-, and 13C-NMR spectroscopic techniques. Lastly, these derivatives were tested for their in vitro urease inhibitory potential. Six compounds among the series attributed excellent inhibition with IC50 values of 7.20±0.59 to 19.61±1.10 μM better than the reference drug thiourea (IC50=22.12±1.20 μM). Similarly, three derivatives showed significant while two compounds showed less inhibitory effects against the urease enzyme. The molecular docking analysis was carried out to reveal the binding modes and types of interaction taking place between protein (urease) and synthesized compounds. The Density Functional Theory (DFT) calculations were performed at B3LYP/6-311++G(d,p) to check the structure stability. For the account of intramolecular interaction, the DFT-D3 and Reduced Density Gradient (RDG) analysis were performed. Furthermore, the chemical nature of all compounds was explored by TD-DFT method using CAM-B3LYP functional with 6-311++G(d,p) basis set. The dynamic simulation as well as MMGBSA studies validated the binding affinity and stability of the ligand receptor complex, displaying main interactions contributing in the biological activity of the product derivatives.

Insights into a photo-driven laccase coupling system for enhanced photocatalytic oxidation and biodegradation

Effective depolymerization of lignin into environmentally friendly aromatic chemicals under mild conditions is gaining interest. Fungal laccase is capable of catalyzing a wide range of reactions, but its low redox potential and preference for acidic pH limit its potential applications. Herein, we developed a laccase-methylene blue (LAC-MB) coupling system, combining the selectivity of enzyme catalysis with the high reactivity of photocatalysis, for the efficient degradation of lignin model compounds. Theoretical calculations indicate that the electron donor’s distance to the LAC’s active site T1 Cu is shortened from 29.7 to 7.3 Å in the LAC-MB. In this system, MB, possessing strong interaction with T1 Cu, acts as a light absorber, enabling the rapid transfer of photogenerated electrons to T1 Cu. This significantly enhances the degradation rate of guaiacol (GUA) from 28.8 % to 91.46 %. The LAC-MB can oxidize both phenolic and non-phenolic lignin model compounds under red-LED irradiation with wide pH ranging from 3.0 to 7.0 and high-efficiency. By tuning the primary coordination sphere and the access tunnel of T1 Cu, we further revealed that enhanced binding affinity and active site accessibility for the LAC-MB complex attributed to the photocatalysis’s high reactivity. Based on this, LAC variants with enhanced binding capabilities were constructed and the resulting mutant LAC-MB are characterized by higher oxygen consumption and ROS generation activated by red-LED, specifically a higher quantum yield of 1O2, demonstrating increased electron transfer and light-driven reactivity. This photo-enzyme coupling system presents a new pathway for the high-efficiency processing of lignocellulosic biomass and offers insights for designing future artificial photosynthetic systems.

Inhibition of Key Virulence Enzymes of Botrytis cinerea by Flavonoids from the Antarctic Plant Colobanthus quitensis.

This study investigates the antifungal efficacy of flavonoids derived from Colobanthus quitensis against key virulence-related enzymes implicated in the pathogenic mechanisms of Botrytis cinerea. The flavonoids swertiajaponin, schaftoside, vitexin, and saponarin significantly inhibited pectinase, cellulase, and laccase activity. Specifically, swertiajaponin showed mixed inhibition of pectinase and cellulase, characterized by high affinity (low inhibition constant -Ki-) for enzyme-substrate complexes. Schaftoside showed mixed inhibition of pectinase and competitive inhibition of laccase, effectively reducing enzymatic activity by competing directly with the substrate. In contrast, vitexin showed competitive inhibition of pectinase and non-competitive inhibition of laccase, suggesting it induces conformational changes within the enzyme. Finally, saponarin uniquely showed uncompetitive inhibition of laccase, stabilizing the enzyme-substrate complex and thereby markedly reducing catalytic turnover. Supported by kinetic parameters (maximum velocity -Vmax-, Michaelis constant -Km-, and Ki), these findings highlight the potential of flavonoids from C. quitensis as natural fungicides, offering a sustainable and eco-friendly alternative to synthetic fungicides for managing agricultural diseases.

Structural and Solution Speciation Studies on fac-Tricarbonylrhenium(I) Complexes of 2,2'-Bipyridine Analogues.

In this study, we report the synthesis and characterization of 12 novel rhenium(I) complexes with the general formula fac-[Re(CO)3(NN)X]n+ where (NN) is a 2,2'-bipyridine analogue ligand, X = Cl-, Br-, or H2O, and n = 0 or 1, focusing on their speciation in an aqueous solution. The prepared organorhenium complexes are stable in a wide pH range in an aqueous solution, and no release of the bidentate ligands or the carbonyl ligands was observed. The stability of the complexes in various biologically relevant matrices (cell culture medium and real blood serum) was also demonstrated. However, the simultaneous substitution of the halido ligand by water and slow hydrolysis of the ester bonds in the ligands were observed, affecting both the solubility and the lipophilicity of the compounds. The aqua complexes became more lipophilic in the presence of chloride ions, while the hydrophilicity increased significantly with time due to the hydrolysis of the ester bonds, which probably contributed to their weak pharmacological activity. The results also showed kinetically hindered aqueous solvation of the halido complexes and low chloride ion affinity of the aqua complexes. The deprotonation of the coordinated aqua ligand in the complexes occurs in the pH = 7-10 range, leading to significant formation (18-30%) of hydroxido species at pH = 7.4. The halido complexes showed somewhat higher cytotoxicity (IC50 = 60-99 μM) on human colon adenocarcinoma cancer cells (Colo205 and Colo320) than the corresponding aqua complexes (IC50 > 100 μM). In all cases, no antibacterial effect was observed (MIC > 100 μM), but some of the complexes showed moderate antiviral activity (IC50 ∼ 50 μM) on Herpes simplex virus 2.

In-silico and in-vitro studies to identify potential inhibitors of SARS-CoV-2 spike protein from Omani medicinal plants

In the quest for novel therapeutic agents against SARS-CoV-2, the proposed study explores the potential of traditional Omani medicinal plants, focusing on the efficacy of natural ligands against the virus's Spike protein. Among 437 identified medicinal plants across Oman, 47 species that are documented for their traditional use in treating respiratory infections, with 30 species' ligands available were chosen for analysis. Molecular docking was performed using Autodock Vina on these ligands, yielding 406 unique ligands post-duplication removal. The binding affinities of target-ligand complexes were precisely determined, ranking them by interaction strength. This process identified Corilagin, a phytochemical from the Acalypha indica plant (locally known as Aeyan Al Aqrada), as the most promising inhibitor. Subsequent analyses using GROMACS for molecular dynamics simulation confirmed its binding stability and interaction dynamics of the Corilagin-protein complex. The in-vitro studies further validated Corilagin's inhibitory effect on SARS-CoV-2, demonstrating a remarkable 92 % inhibition at 0.5 mM concentration. Dilution studies to ascertain the IC50 value revealed Corilagin's high potency at a micromolar level (IC50 = 2.15 ± 0.13 μM), underscoring its potential as a drug candidate for SARS-CoV-2 treatment. These findings highlight the significance of ethnomedicine and in-silico methodologies in drug discovery, offering promising directions for future antiviral research.

Ensembling methods for protein-ligand binding affinity prediction

Protein-ligand binding affinity prediction is a key element of computer-aided drug discovery. Most of the existing deep learning methods for protein-ligand binding affinity prediction utilize single models and suffer from low accuracy and generalization capability. In this paper, we train 13 deep learning models from combinations of 5 input features. Then, we explore all possible ensembles of the trained models to find the best ensembles. Our deep learning models use cross-attention and self-attention layers to extract short and long-range interactions. Our method is named Ensemble Binding Affinity (EBA). EBA extracts information from various models using different combinations of input features, such as simple 1D sequential and structural features of the protein-ligand complexes rather than 3D complex features. EBA is implemented to accurately predict the binding affinity of a protein-ligand complex. One of our ensembles achieves the highest Pearson correlation coefficient (R) value of 0.914 and the lowest root mean square error (RMSE) value of 0.957 on the well-known benchmark test set CASF2016. Our ensembles show significant improvements of more than 15% in R-value and 19% in RMSE on both well-known benchmark CSAR-HiQ test sets over the second-best predictor named CAPLA. Furthermore, the superior performance of the ensembles across all metrics compared to existing state-of-the-art protein-ligand binding affinity prediction methods on all five benchmark test datasets demonstrates the effectiveness and robustness of our approach. Therefore, our approach to improving binding affinity prediction between proteins and ligands can contribute to improving the success rate of potential drugs and accelerate the drug development process.

Unwinding DNA strands by single-walled carbon nanotubes: Molecular docking and MD simulation approach

Despite the growing research into the use of carbon nano-tubes (CNTs) in science and medicine, concerns about their potential toxicity remain insufficiently studied. This study utilizes molecular docking calculations combined by molecular dynamics simulations to investigate the dynamic intricacies of the interaction between single-walled carbon nanotubes (swCNTs) and double-stranded DNA (dsDNA). By examining the influence of swCNT characteristics such as length, radius, and chirality, our findings shed light on the complex interplay that shapes the binding affinity and stability of the dsDNA-swCNT complex. Molecular docking results identify a zigzag swCNT, with a radius of 0.16 Å and a length of 38 Å, as exhibiting the highest binding affinity with dsDNA (−23.9 kcal/mol). Comprehensive analyses, spanning docking results, binding energies, RMSD, radius of gyration, and potential of mean force (PMF) profiles, provide a detailed understanding of the denaturation dynamics. The PMF profiles reveal the thermodynamic feasibility of the DNA-CNT interaction, outlining distinct energy landscapes and barriers: when the selected swCNT binds within the dsDNA groove, the system becomes trapped at the first and second local energy minima, occurring at 1.48 nm and 1.00 nm, respectively. Intramolecular hydrogen bond calculations show a significant reduction, affirming the denaturing effect of swCNTs on DNA. Furthermore, the study reveals a significant reduction in the binding affinity of Ethidium Bromide (EB) to dsDNA following its interaction with swCNT, with a decrease in EB binding to dsDNA of approximately 13.2 %. This research offers valuable insights into the toxic effects of swCNTs on dsDNA, contributing to a rationalization of the cancerous potential of swCNTs.

Deciphering Pathways and Thermodynamics of Protein Assembly Using Native Mass Spectrometry.

Protein oligomerization regulates many critical physiological processes, and its dysregulation can contribute to dysfunction and diseases. Elucidating the assembly pathways and quantifying their underlying thermodynamic and kinetic parameters are crucial for a comprehensive understanding of biological processes and for advancing therapeutics targeting abnormal protein oligomerization. Established binding assays, with limited mass precision, often rely on simplified models for data interpretation. In contrast, high-resolution native mass spectrometry (nMS) can directly determine the stoichiometry of biomolecular complexes in vitro. However, quantification is hindered by the fact that the relative abundances of gas-phase ions generally do not reflect solution concentrations due to nonuniform response factors. Recently, slow mixing mode (SLOMO)-nMS, which can quantify the relative response factors of interacting species, has been demonstrated to reliably measure the affinity (Kd) of binary biomolecular complexes. Here, we introduce an extended form of SLOMO-nMS that enables simultaneous quantification of the thermodynamics in multistep association reactions. Application of this method to homo-oligomerization of concanavalin A and insulin confirmed the reliability of the assay and uncovered details about the assembly processes that had previously resisted elucidation. Results acquired using SLOMO-nMS implemented with charge detection shed new light on the binding of recombinant human angiotensin-converting enzyme 2 and the SARS-CoV-2 spike protein. Importantly, new assembly pathways were uncovered, and the affinities of these interactions, which regulate host cell infection, were quantified. Together, these findings highlight the tremendous potential of SLOMO-nMS to accelerate the characterization of protein assembly pathways and thermodynamics and, in so doing, enhance fundamental biological understanding and facilitate therapeutic development. https://orcid.org/0000-0002-3389-7112.

Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2.

Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein-protein interactions in signaling pathways.

Cone Angles Quantify and Predict the Affinity and Reactivity of Anion Complexes between Trifluoroborates and Rigid Macrocycles.

Steric manipulation is a known concept in molecular recognition but there is currently no linear free energy relationship correlating sterics to the stability of receptor-anion complexes nor to the reactivity of the bound anion. By analogy to Tolman cone angles in cation coordination chemistry, we explore how to define and correlate cone angles of organo-trifluoroborates (R-BF3 -) to the affinities observed for cyanostar-anion binding. We extend the analogy to a rare investigation of the anion's reactivity and how it changes upon binding. The substituent on the anion is used to define the cone angle, θ. A series of 10 anions were studied including versions with ethynyl, ethylene, and ethyl substituents to tune steric bulk across the sp, sp2 and sp3 hybridized α-carbons bearing 0, 1 and 2 hydrogen atoms. A linear relationship between affinity and cone angle is observed for anions bearing substituents larger than the -BF3 - headgroup. This correlation predicted affinities of two new anions to within ±5 %. We explored how complexation affects the reactivity of fluoride exchange. The yield of fluoride transfer from R-BF3 - to Lewis acid triphenylborane is correlated with cone angle. We predict that other rigid macrocycles, like commercially available bambusuril, could follow these trends.

An Insight Into Experimental and Theoretical Investigation of Structure, Photophysical Property by ESIPT Processes and Biological Activities of Schiff Base Copper Complex

ABSTRACTA novel Schiff base (BSSMO) and its copper complex have been synthesized, and their structure was delineated using single crystal XRD studies. Computational techniques were used to design and evaluate BSSMO‐based luminophores, revealing a significant intramolecular hydrogen bond within the molecule. Understanding ESIPT is crucial for optimizing photophysical and luminophore properties of organic molecules, especially for advancing optoelectronic devices. The study also explored the mechanisms of GSIPT and ESIPT for these BSSMO‐based luminophores using transition state theory, charge distribution, molecular orbital analysis, and quantum theory of atoms in molecules. Results advocated that BSSMO‐L2 exhibits higher absorption compared with BSSMO‐L1 and the same trend is observed in emission spectral studies. However, the intensity of enol emissions in BSSMO‐L2 is lower than that of keto (BSSMO‐L3) emissions and the S1 (Keto form) emission of BSSMO‐L3 shows significantly larger values, making it attractive for optoelectronic devices. The findings offer valuable insights for the development of ESIPT emitters with distinct photophysical properties. The in silico antidiabetic study of BSSMO‐L2 explores the interaction with PPAR‐γ protein, revealing a moderate affinity and stable complex, enhancing its bio‐potential for future applications. The in vitro anticancer study of Cu‐BSSMO‐L2 complex shows a potential anticancer effect through mitochondrial and extrinsic death receptor mediated pathways. These insights contribute to the design of novel benzenesulfonamide‐based bioactive molecules.

Synthesis, crystal structure, DNA/protein interactions and cytotoxicity studies of tridentate ligand based Cu(II) complexes with various amine co-ligands

The present study utilizes a tridentate ligand H2L (1) derived as a condensation product of dehydroacetic acid and 2-furoic acid hydrazide for the synthesis of a series of copper complexes, namely [Cu(L)(bipy)] (3), [Cu(L)(4,4′-Me2-bipy)] (4), [Cu(L)(6,6′-Me2-bipy)] (5), [Cu(L)(phen)] (6), [Cu(L)(2,9-Me2-phen)] (7) [Cu(L)(pyrazino[2,3]phen)] (8) [Cu(L)(2,2′-dipyridylamine)] (9) [Cu(L)(diphenylmethanamine)] (10), obtained by reacting Cu(acetate)2 with the doubly deprotonated ligand and a range of co-ligand amines. All the synthesized compounds were fully structurally characterized using IR, 1H NMR, HRMS and single-crystal X-ray diffraction studies. The thermal stability and decomposition pattern was investigated using TGA studies. The bio-efficacy of the developed ligand and its complexes was evaluated in anti-cancer assay against SKOV3 cell lines. Copper complexes have been extensively studied for their potential to generate anticancer properties. Most complexes comprise mixed ligands, such as N-N-chelating heterocycles like 2,2’-bipyridine (bpy) and 1,10 phenanthroline (phen), chosen for their chelating and intercalative characteristics. Complex 7 displayed the highest anti-cancer activity with an IC50 value of 0.8 µM compared to standard drug doxorubicin. The impact of complex 7 on DNA fragmentation was also assessed through agarose gel electrophoresis, which indicated that complex 7 promotes observable DNA fragmentation. The serum binding affinity of the complex 7 was also investigated against BSA and HSA protein. The strong binding affinity of complex [Cu(L)(2,9-Me2-phen)] (7) with BSA/HSA and its better stability compared to the other investigated complexes were deduced based on its biological activity. The impact of varying concentrations of complex 7 on BSA and HSA was investigated using absorption spectroscopy, revealing the presence of a dynamic quenching mechanism. In silico molecular dynamics and docking, approaches have been utilized to validate the empirical data derived from serum binding studies.

Relative genotoxicity of polycyclic aromatic hydrocarbons inferred from free energy perturbation approaches

Utilizing molecular dynamics and free energy perturbation, we examine the relative binding affinity of several covalent polycyclic aromatic hydrocarbon - DNA (PAH-DNA) adducts at the central adenine of NRAS codon-61, a mutational hotspot implicated in cancer risk. Several PAHs classified by the International Agency for Research on Cancer as probable, possible, or unclassifiable as to carcinogenicity are found to have greater binding affinity than the known carcinogen, benzo[a]pyrene (B[a]P). van der Waals interactions between the intercalated PAH and neighboring nucleobases, and minimal disruption of the DNA duplex drive increases in binding affinity. PAH-DNA adducts may be repaired by global genomic nucleotide excision repair (GG-NER), hence we also compute relative free energies of complexation of PAH-DNA adducts with RAD4-RAD23 (the yeast ortholog of human XPC-RAD23) which constitutes the recognition step in GG-NER. PAH-DNA adducts exhibiting the greatest DNA binding affinity also exhibit the least RAD4-RAD23 complexation affinity and are thus predicted to resist the GG-NER machinery, contributing to their genotoxic potential. In particular, the fjord region PAHs dibenzo[a,l]pyrene, benzo[g]chrysene, and benzo[c]phenanthrene are found to have greater binding affinity while having weaker RAD4-RAD23 complexation affinity than their respective bay region analogs B[a]P, chrysene, and phenanthrene. We also find that the bay region PAHs dibenzo[a,j]anthracene, dibenzo[a,c]anthracene, and dibenzo[a,h]anthracene exhibit greater binding affinity and weaker RAD4-RAD23 complexation affinity than B[a]P. Thus, the study of PAH genotoxicity likely needs to be substantially broadened, with implications for public policy and the health sciences. This approach can be broadly applied to assess factors contributing to the genotoxicity of other unclassified compounds.

Bioactive flavonoids from Populus ciliata: In vitro and In silico evaluation of antimicrobial, antioxidant and anti-inflammatory activities

The stem bark of Populus ciliata is recognized as a valuable source of medicinal and therapeutic compounds. The study focused on extracting bioactive compounds from the ethyl acetate fraction of P. ciliata stem bark. Four flavonoids were isolated for the first time from the plant: EF01 [3,5-dihydroxy-2-(4-hydroxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one], EF02 [5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one], EF03 [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one] and EF04 [(2S)-5-hydroxy-2- (4- hydroxyphenyl)- 4-oxo- 3,4- dihydro-2H-chromen- 7-yl-2-O-(6-deoxy-α-L-mannopyranosyl)-β-D- glucopyranoside]. These compounds were characterized and evaluated for various biological activities using in vitro and in silico techniques. The findings revealed that EF01 (a flavonol glycoside) and EF04 (a flavanone glycoside) were isolated for the first time from the Populus genus. Among the compounds, EF03 exhibited the strongest biological activities, including antioxidant (IC50: 6.36±1.43 μg/mL; 14.74±1.49 μg/mL), antibacterial (MIC: 6.25-12.50 μg/mL), antifungal (Fusarium oxysporum-6.25 μg/mL; Candida glabrata-15.62 μg/mL), and anti-inflammatory (IC50: 9.39±0.81 μg/mL) activities. Additionally, EF04 demonstrated promising effects against Candida auris (MIC: 31.25 μg/mL). In molecular docking, dynamics stimulations and molecular mechanics-generalized born surface area studies, EF03 showed notable binding affinity (surpassing the positive controls) and stable complexes with human cyclooxygenase-2, human peroxiredoxin 5, N-myristoyl transferase and penicillin-binding protein, reinforcing its potential antioxidant, antimicrobial, and anti-inflammatory properties. In conclusion, the flavonoids extracted from P. ciliata exhibit significant biological activity, which may contribute to its medicinal properties. Further research is warranted to identify additional bioactive phytochemicals from P. ciliata with potential applications in various fields.