Journal of Molecular Recognition最新文献

The in vitro interactions of homopterocarpin, a potent antioxidant and anti-ulcerative isoflavonoid, with human serum albumin (HSA) and human aldehyde dehydrogenase (hALDH) were explored using various spectroscopic methods, in silico and molecular dynamic (MD) studies. The result showed that homopterocarpin quenched the intrinsic fluorescences of HSA and hALDH. The interactions were entropically favorable, driven primarily by hydrophobic interactions. The proteins have one binding site for the isoflavonoid. This interaction  increased the proteins hydrodynamic radii by over 5% and caused a slight change in HSA surface hydrophobicity Homopterocarpin preferentially binds to HSA subdomain IB with a binding affinity of −10.1 kcal/mol before interaction stoke with hALDH (–8.4 kcal/mol). HSA-homopterocarpin complex attained pharmacokinetic-pharmacodynamics reversible equilibration time faster than ALDH-homopterocarpin. However, the probable and eventual therapeutic effect of homopterocarpin is the mixed inhibition ALDH activity having a K_i value of 20.74 μM. The MD results revealed the stabilization of the complex in HSA–homopterocarpin and ALDH–homopterocarpin from their respective spatial structures of the complex. The findings of this research will provide significant benefits in understanding the pharmacokinetics characteristics of homopterocarpin at the clinical level.

Mitochondria are the main sites of oxidative metabolism and energy release of sugars, fats and amino acids in the body. According to studies, malignant tumor occurrence and development have been linked to abnormal mitochondrial energy metabolism (MEM). However, the feasible role of abnormal MEM in colon adenocarcinoma (COAD) is poorly understood. In this work, we obtained COAD patient data from The Cancer Genome Atlas (TCGA) as the training set, and GSE103479 from Gene Expression Omnibus (GEO) as the validation set. Combined with the mitochondrial energy metabolic pathway (MEMP)-related genes in Kyoto Encyclopedia of Genes and Genomes (KEGG) database, a risk prognostic model was constructed by utilizing Cox regression analysis to identify 6 feature genes (CYP4A11, PGM2, PKLR, PPARGC1A, CPT2 and ACAT2) that were significantly associated with MEMP in COAD. By stratifying the samples based on riskscore, two distinct groups, namely the high- and low-risk groups, were identified. The model demonstrated accurate assessment of the prognosis risk in COAD patients and exhibited independent prognostic capability, as evidenced by the survival curve and receiver operating characteristic (ROC) curve analysis. A nomogram was plotted based on clinical information and riskscore. We proved it could predict the survival time of COAD patients effectively combined with the calibration curve of risk prediction. Subsequently, based on the immune evaluation and mutation frequency analysis performed on COAD patients, patients in high-risk group had observably higher immune scores, immune activity and PDCD1 expression level than low-risk group. In general, the prognostic model developed using MEMP-related genes served as a valuable biomarker for forecasting the prognosis of COAD patients, which offered a reference for the prognosis evaluation and clinical cure of COAD patients.

Prostate adenocarcinoma (PRAD) is the second leading cause of death in men and the key factor that attributes to the severity and higher mortality rates is the tumor's ability to promote osteoblastic metastases (OM). Currently, no blood-based biomarkers are present that bridges the crosstalk between PRAD and OM progression. Conversely, circulatory microRNAs (miRNAs) are gaining interest among the scientific community for its potential as blood-based markers for cancer detection. Using computational pipeline, this study screened exosome-based miRNA that is functionally regulating OM in PRAD. We retrieved the expression profile of miRNA, mRNA from PRAD microarray, and RNA-Seq samples deposited in global repositories and identified the differentially expressed miRNAs (DEMs) and differentially expressed genes. Thereafter, the average expression of the miRNAs was identified in extracellular vesicle specifically in exosomes. Survival analysis and clinical profiling identified functionally significant miR-92a-3p to be a key factor in OM. This was further examined by the interactions with various noncoding RNA elements, transcription factors, oncogenes, tumor suppressor genes, and protein kinases regulated by miR-92a-3p. Identifying the expression pattern, nodal metastasis, Gleason score, and hazard ratio deciphered the critical role of the targets regulated by miR-92a-3p. Further, binding association analyzed through energy, seed match and accessibility showed the miRNA-targets involved in cytokine, TGF-β, and Wnt signaling having close regulatory role in promoting OM. Our findings highlight the potent role of miR-92a-3p as blood-based diagnostic biomarker for OM. The comprehensive insights from our study can be elemental in designing diagnostic biomarker for PRAD.

A novel Schiff base has been synthesized from the condensation of the 3-formyl-2-hydroxybenzoic acid and 4-nitrobenzene-1,2-diamine. The new ligand was found to have two coordination sites. So, it has the capability to form mono- and binuclear complexes with different metal ions. The free ligand and its mono- and binuclear cobalt(II) complexes have been characterized by UV–Visible spectra, IR, elemental analyzes, H¹ NMR, conductimetric, thermal, and magnetic measurements. Results indicated that the cobalt(II) ion is attached to the inside coordination site and the second metal ion attached to the outside coordination site. The complexes are all non-electrolytes, as demonstrated by the molar conductance tests. The thermodynamic parameters of the metal complexes are calculated using Horowitz Metzger and Coats-Redfern methods. The complexes' bonding properties have also been estimated. Molecular docking was employed to forecast the interaction of the prepared with the Candida-albicans receptor (1zap). The biological activities of these metal complexes were tested against some bacteria and fungi. It is evident from the biological screening data that the prepared Co(II) binuclear complexes exhibit predominant activity against Candida albicans, Penicillium oxalicum and Escherichia coli, while they have no activity against Micrococcus roseus and Micrococcus luteus.

Binding interactions between Cibacron Blue-F3GA (CB-F3GA) and human serum albumin (HSA, at physiologically ten-fold lower concentration) was studied by isothermal titration calorimetry (ITC) and in-silico docking computations. ITC experiments revealed two separate binding sites on HSA with different binding affinities for CB-F3GA. The high-affinity binding site (PBS-II) on HSA binds CB-F3GA at nanomolar scale (K_D1 = 118 ± 107 nM) with favorable binding enthalpy (ΔH^o₁ = − 6.47 ± 0.44 kcal/mol) and entropy (−TΔS^o₁ = −2.98 kcal/mol) energies. CB-F3GA binds to the low-affinity binding site (PBS-I) at μM scale (K_D2 = 31.20 ± 18.40 μM) with favorable binding enthalpy (ΔH^o₁ = − 5.03 ± 3.86 × 10⁻² kcal/mol) and entropy (−TΔS^o₁ = −1.12 kcal/mol) energies. ITC binding data strongly suggest that CB-F3GA binding to PBS-II site increases the formation of dimeric-HSA clusters (N₁ = 2.43 ± 0.50), while binding to PBS-I leads to tetrameric-HSA clusters (N₂ = 4.61 ± 0.90). These results suggest that a higher degree of HSA aggregation upon drug binding may be expected under physiological conditions, a notion that should be further investigated for the delivery and toxicity of drug−HSA interactions.

The introduction of small ligands to stabilise G-quadruplex DNA structures is a promising method for developing anti-cancer drugs. It is challenging to stabilise the G-quadruplex structure, which can take on a variety of topologies and is known to inhibit specific biological processes. To achieve this, 4-nitrobenzylidene curcumin (NBC), the Knoevenagel condensate of curcumin, was synthesized and characterized. The interaction of 4-nitrobenzylidene curcumin with parallel (c-MYC) and hybrid (H-telo) G-quadruplex structures was studied by circular dichroism (CD) spectroscopy, UV-thermal melting, differential scanning calorimetry (DSC), absorption spectroscopy, fluorescence spectroscopy and docking studies. The outcome demonstrates that, in a K⁺-rich solution, the ligand NBC can stabilise the parallel c-MYC and hybrid H-telo G-quadruplex structures by 5°C. The absorption and fluorescence studies show that the ligand NBC binds to c-MYC and H-telo with affinities of 0.3 × 10⁶ M⁻¹ and 0.6 × 10⁶ M⁻¹, respectively. The ligand interacts with the terminal G-quartet of the quadruplex structure via intercalation and the groove mode of binding, well supported by docking studies as well. NBC has more potent antioxidant activity as compared to the curcumin and 4-nitro benzaldehyde. It was also found to have higher cytotoxic activity towards cell line such as HeLa and MCF-7, while less cytotoxic for healthy Vero cells. Overall, the results show that the Knoevenagel product of curcumin can work better as a G-quadruplex binder and could be used as a possible treatment.

Cyclooxygenase, also known as prostaglandin H2 synthase (PGH2), is one of the most important enzymes in pharmacology because inhibition of COX is the mechanism of action of most nonsteroidal anti-inflammatory drugs. In this study, ten thiazole derivative compounds had synthesized. The analysis of the obtained compounds was performed by ¹H NMR and ¹³C NMR methods. By this method, the obtained compounds could be elucidated. The inhibitory effect of the obtained compounds on cyclooxygenase (COX) enzymes was investigated. The encoded compounds 5a, 5b, and 5c were found to be the most potent compared to the reference compounds ibuprofen (IC₅₀ = 5.589 ± 0.278 μM), celecoxib (IC₅₀ = 0.132 ± 0.004 μM), and nimesulide (IC₅₀ = 1.692 ± 0.077 μM)against COX-2 isoenzyme. The inhibitory activity of 5a, 5b, and 5c is approximate, but the 5a derivative proved to be the most active in the series with an IC₅₀ value of 0.180 ± 0.002 μM. The most potent COXs inhibitor was 5a, which was further investigated for its potential binding mode by a molecular docking study. Compound 5a was found to be localized at the active site of the enzyme, like celecoxib, which has a remarkable effect on COXs enzymes.

α₁-Acid glycoprotein (AGP) is a prominent acute phase component of blood plasma and extravascular fluids. As a member of the immunocalins, AGP exerts protective effects against Gram-negative bacterial infections but the underlying molecular mechanisms still need to be elucidated. Notably, the chemical structures of phenothiazine, phenoxazine and acridine type ligands of AGP are similar to those of phenazine compounds excreted by the opportunistic human pathogen Pseudomonas aeruginosa and related bacterial species. These molecules, like pyocyanin, act as quorum sensing-associated virulence factors and are important contributors to bacterial biofilm formation and host colonisation. Molecular docking simulations revealed that these agents fit into the multi-lobed cavity of AGP. The binding site is decorated by several aromatic residues which seem to be essential for molecular recognition of the ligands allowing multifold π–π and CH–π interactions. The estimated affinity constants (~10⁵ M⁻¹) predict that these secondary metabolites could be trapped inside the β-barrel of AGP which in turn could reduce their cytotoxic effects and disrupt the microbial QS network, facilitating the eradication of bacterial infections.

Based on the synergistic action of hydrogen bond and electrostatic interaction, provided by methacrylic acid and 2-aminoethyl ester hydrochloride (FM2), respectively, novel molecularly imprinted polymers (SA-MIPs) were designed to improve its selective recognition ability. Diclofenac sodium (DFC) was chosen as the template molecule of this study. The interaction and their recognition sites between two functional monomers and templates were confirmed by nuclear magnetic resonance hydrogen spectroscopy. Because of the synergistic action of hydrogen bond and electrostatic interaction, the imprinting factor (IF) of SA-MIPs (IF = 2.26) is superior to the corresponding monofunctional monomer imprinting materials (IF = 1.52, 1.20) and the materials using two functional monomers with an only single type of interaction (IF = 1.54, 1.75). The results of selective adsorption experiments indicate that the selective recognition ability of SA-MIPs is significantly better than that of the other four MIPs, and the difference in selectivity coefficient for methyl orange is the largest between SA-MIPs and the MIPs only using FM2, which is about 70 times. In addition, x-ray photoelectron spectroscopy was used to verify the interaction between SA-MIPs and the template. This work and its explanation of the interaction mechanism at the molecular level will be helpful for the rational design of novel MIPs with higher selectivity. Besides, SA-MIPs have good adsorption performance (37.75 mg/g) for DFC in aqueous solutions, which could be used as potential adsorption materials for the effective removal of DFC in the aquatic environment.