Integrating Computational and Experimental Methods to Identify Novel Sweet Peptides from Egg and Soy Proteins.

Sweetness in food delivers a delightful sensory experience, underscoring the crucial role of sweeteners in the food industry. However, the widespread use of sweeteners has sparked health concerns. This underscores the importance of developing and screening natural, health-conscious sweeteners. Our study represents a groundbreaking venture into the discovery of such sweeteners derived from egg and soy proteins. Employing virtual hydrolysis as a novel technique, our research entailed a comprehensive screening process that evaluated biological activity, solubility, and toxicity of the derived compounds. We harnessed cutting-edge machine learning methodologies, specifically the latest graph neural network models, for predicting the sweetness of molecules. Subsequent refinements were made through molecular docking screenings and molecular dynamics simulations. This meticulous research approach culminated in the identification of three promising sweet peptides: DCY(Asp-Cys-Tyr), GGR(Gly-Gly-Arg), and IGR(Ile-Gly-Arg). Their binding affinity with T1R2/T1R3 was lower than -15 kcal/mol. Using an electronic tongue, we verified the taste profiles of these peptides, with IGR emerging as the most favorable in terms of taste with a sweetness value of 19.29 and bitterness value of 1.71. This study not only reveals the potential of these natural peptides as healthier alternatives to traditional sweeteners in food applications but also demonstrates the successful synergy of computational predictions and experimental validations in the realm of flavor science.

Structure and properties of metal-organic frameworks modulated by sulfate ions.

Anions play a significant role in the construction of metal-organic frameworks (MOFs). Anions can affect coordination between metal ions and organic ligands, and the formation of crystal structures, thereby affecting the structure and properties of MOFs. Two novel 3D porous MOFs ({[Cd3(TIPE)2(SO4)1.6(H2O)2.4]·2.8OH·6.2H2O}n (MOF-1) and {[Cd3(TIPE)2(SO4)3(H2O)2]·10H2O}n (MOF-2)) were successfully synthesized, by introducing SO42- to design and adjust their structure and properties, in which the sulfate ions not only participated in coordination but also played a bridging role. Both MOF-1 and MOF-2 exhibited high stability and strong fluorescence properties, and their fluorescence properties also changed compared to those of previously reported 2D nonporous MOF-3 ({[Cd2(TIPE)2Cl3(ACN)]·CdCl3·3H2O}n) with an identical ligand. They could also be used in combination with MOF-3 to distinguish between Fe3+ and Cr2O72- ions, due to a change in their fluorescence properties. In this work, the structure was reshaped by introducing sulfate ions, and the role and function of the sulfate ions in the structure were studied, providing a feasible idea for the design and precise regulation of MOFs.

Functional Materials for Water Restoration: A "Fish Cage" for Efficient Capture of Pb(II) Ions.

In this work, a "fish cage" material for trapping Pb(II) ions has been successfully obtained, which is a novel clathrate functionalized metal-oganic framework (Cage-MOF) by introducing free adsorption sites (SO42-). The three-dimensional (3D) cage structure of Cage-MOF gives it a larger contact area and can capture "swimming fish" (Pb(II)) like a "fishing cage" in a water solution. This is the first high-efficiency adsorption material obtained by introducing free coordination groups. Cage-MOF not only has excellent water stability but also improves the selectivity and affinity for Pb(II) ions in water because of the presence of sulfate adsorption sites, and its adsorption capacity is as high as 806 mg/g. This work shows a novel and effective idea for the synthesis of water restoration materials.

Challenges and opportunities for improving the druggability of natural product: Why need drug delivery system?

Bioactive natural products (BNPs) are the marrow of medicinal plants, which are the secondary metabolites of organisms and have been the most famous drug discovery database. Bioactive natural products are famous for their enormous number and great safety in medical applications. However, BNPs are troubled by their poor druggability compared with synthesis drugs and are challenged as medicine (only a few BNPs are applied in clinical settings). In order to find a reasonable solution to improving the druggability of BNPs, this review summarizes their bioactive nature based on the enormous pharmacological research and tries to explain the reasons for the poor druggability of BNPs. And then focused on the boosting research on BNPs loaded drug delivery systems, this review further concludes the advantages of drug delivery systems on the druggability improvement of BNPs from the perspective of their bioactive nature, discusses why BNPs need drug delivery systems, and predicts the next direction.

Machine Learning Assisted Discovery of Novel p38α Inhibitors from Natural Products.

BACKGROUND: P38α, emerging as a hot spot for drug discovery, is a member of the mitogen- activated protein kinase (MAPK) family and plays a crucial role in regulating the production of inflammatory mediators. However, despite a massive number of highly potent molecules being reported and several under clinical trials, no p38α inhibitor has been approved yet. There is still demand to discover novel p38α to deal with the safety issue induced by off-target effects. OBJECTIVE: In this study, we performed a machine learning-based virtual screening to identify p38α inhibitors from a natural products library, expecting to find novel drug lead scaffolds. METHODS: Firstly, the training dataset was processed with similarity screening to fit the chemical space of the natural products library. Then, six classifiers were constructed by combing two sets of molecular features with three different machine learning algorithms. After model evaluation, the three best classifiers were used for virtual screening. RESULTS: Among the 15 compounds selected for experimental validation, picrasidine S was identified as a p38α inhibitor with the IC50 as 34.14 µM. Molecular docking was performed to predict the interaction mode of picrasidine S and p38α, indicating a specific hydrogen bond with Met109. CONCLUSION: This work provides a protocol and example for machine learning-assisted discovery of p38α inhibitor from natural products, as well as a novel lead scaffold represented by picrasidine S for further optimization and investigation.

InflamNat: web-based database and predictor of anti-inflammatory natural products.

Natural products (NPs) are a valuable source for anti-inflammatory drug discovery. However, they are limited by the unpredictability of the structures and functions. Therefore, computational and data-driven pre-evaluation could enable more efficient NP-inspired drug development. Since NPs possess structural features that differ from synthetic compounds, models trained with synthetic compounds may not perform well with NPs. There is also an urgent demand for well-curated databases and user-friendly predictive tools. We presented a comprehensive online web platform (InflamNat, http://www.inflamnat.com/ or http://39.104.56.4/ ) for anti-inflammatory natural product research. InflamNat is a database containing the physicochemical properties, cellular anti-inflammatory bioactivities, and molecular targets of 1351 NPs that tested on their anti-inflammatory activities. InflamNat provides two machine learning-based predictive tools specifically designed for NPs that (a) predict the anti-inflammatory activity of NPs, and (b) predict the compound-target relationship for compounds and targets collected in the database but lacking existing relationship data. A novel multi-tokenization transformer model (MTT) was proposed as the sequential encoder for both predictive tools to obtain a high-quality representation of sequential data. The experimental results showed that the proposed predictive tools achieved an AUC value of 0.842 and 0.872 in the prediction of anti-inflammatory activity and compound-target interactions, respectively.

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors.

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents.

As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC50 against HDAC1 is 1.14 µM), with no activity against HDAC8. In J774A.1 macrophage, compound 1-3, 13 and 17-19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1ß production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1ß maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation.

Study on the Local Structure and Luminescence Properties of a Y2Mg2Al2Si2O12:Eu3+ Red Phosphor for White-Light-Emitting Diodes.

Structure determines properties, and properties determine applications, which is an important ideology of natural sciences. For optical materials, it is vital to lucubrate the corresponding relationship between the local crystal structure and luminescence properties for their design, synthesis, and application. This work reports a newly designed Y2Mg2Al2Si2O12(YMAS):Eu3+ red phosphor, in which difunctional Eu3+ ion is used as a red-light activator and spectroscopic probe. The qualitative and quantitative studies on the relationship between the local crystal structure and the luminescence properties of YMAS:Eu3+ are performed experimentally and computationally, using the Y3Al5O12 (YAG):Eu3+ as contrast. Moreover, compared with YAG:Eu3+, the newly designed YMAS:Eu3+ has stronger luminescence, superior Commission Internationale de L'Eclairage chromaticity coordinates, a lower optimal doping concentration, and equally excellent thermal stability. The satisfactory color-rendering index of packaged white-light-emitting diodes demonstrates its potential performance as a red phosphor. Briefly, this work provides not only a new case for the study of the local crystal structure and luminescence properties but also a new possibility for the application of a red phosphor in solid-state lighting.

Dual-Additive Assisted Chemical Vapor Deposition for the Growth of Mn-Doped 2D MoS2 with Tunable Electronic Properties.

Doping of bulk silicon and III-V materials has paved the foundation of the current semiconductor industry. Controlled doping of 2D semiconductors, which can also be used to tune their bandgap and type of carrier thus changing their electronic, optical, and catalytic properties, remains challenging. Here the substitutional doping of nonlike element dopant (Mn) at the Mo sites of 2D MoS2 is reported to tune its electronic and catalytic properties. The key for the successful incorporation of Mn into the MoS2 lattice stems from the development of a new growth technology called dual-additive chemical vapor deposition. First, the addition of a MnO2 additive to the MoS2 growth process reshapes the morphology and increases lateral size of Mn-doped MoS2 . Second, a NaCl additive helps in promoting the substitutional doping and increases the concentration of Mn dopant to 1.7 at%. Because Mn has more valance electrons than Mo, its doping into MoS2 shifts the Fermi level toward the conduction band, resulting in improved electrical contact in field effect transistors. Mn doping also increases the hydrogen evolution activity of MoS2 electrocatalysts. This work provides a growth method for doping nonlike elements into 2D MoS2 and potentially many other 2D materials to modify their properties.

Gefitinib combined with stereotactic radiosurgery in previously treated patients with advanced non-small cell lung cancer.

BACKGROUND: Disease progression remains the major challenge in the management of advanced (stage IIIb or IV) non-small cell lung cancer (NSCLC) after the failure of first-line or second-line chemotherapy, or even of targeted therapies such as gefitinib. The current study evaluated the tolerability and efficacy of stereotactic body radiation therapy (SBRT) in combined with gefitinib as a second-line or third-line treatment in patients with advanced NSCLC. METHODS: Fourteen advanced NSCLC patients showing disease progression after platinum-based chemotherapy regimens were recruited. Eligible patients started taking gefitinib (250 mg/d) 7 days before SBRT and continued for 1 year until disease progression, unacceptable toxicity or withdrawal of consent. SBRT was delivered in median 3 fractions within 3 to 5 days. Treatment-associated toxicity was assessed according to the Common Terminology Criteria for Adverse Events (v.3.0). Local control was assessed according to the Response Evaluation Criteria in Solid Tumors criteria and symptom assessments were measured by the Functional Assessment of Cancer Therapy-Lung instrument (V4.0). RESULTS: With an overall median follow-up of 15.5 months (range, 4 to 27 mo), most patients were well tolerated with common side effects from grade 1 to 2. No grade 4 or higher toxicity was encountered. The clinical disease-related symptom improvement rate was reached 57.1% with the median duration of symptom improvement of 8.0 months. The 1-year local control and overall survival (OS) rates were 83.9% and 69.6%, respectively. The median progression-free survival and OS were 7.0 and 19.0 months, respectively. CONCLUSIONS: The SBRT combined with gefitinib is a promising treatment strategy for advanced (stage IIIb or IV) NSCLC after the failure of previously chemotherapy. This method improves local control and disease-related symptoms with tolerated toxicity, and even increases the progression-free survival and OS.