DiffPROTACs is a deep learning-based generator for proteolysis targeting chimeras.

PROteolysis TArgeting Chimeras (PROTACs) has recently emerged as a promising technology. However, the design of rational PROTACs, especially the linker component, remains challenging due to the absence of structure-activity relationships and experimental data. Leveraging the structural characteristics of PROTACs, fragment-based drug design (FBDD) provides a feasible approach for PROTAC research. Concurrently, artificial intelligence-generated content has attracted considerable attention, with diffusion models and Transformers emerging as indispensable tools in this field. In response, we present a new diffusion model, DiffPROTACs, harnessing the power of Transformers to learn and generate new PROTAC linkers based on given ligands. To introduce the essential inductive biases required for molecular generation, we propose the O(3) equivariant graph Transformer module, which augments Transformers with graph neural networks (GNNs), using Transformers to update nodes and GNNs to update the coordinates of PROTAC atoms. DiffPROTACs effectively competes with existing models and achieves comparable performance on two traditional FBDD datasets, ZINC and GEOM. To differentiate the molecular characteristics between PROTACs and traditional small molecules, we fine-tuned the model on our self-built PROTACs dataset, achieving a 93.86% validity rate for generated PROTACs. Additionally, we provide a generated PROTAC database for further research, which can be accessed at https://bailab.siais.shanghaitech.edu.cn/service/DiffPROTACs-generated.tgz. The corresponding code is available at https://github.com/Fenglei104/DiffPROTACs and the server is at https://bailab.siais.shanghaitech.edu.cn/services/diffprotacs.

The nature of proton-coupled electron transfer in a blue light using flavin domain.

Proton-coupled electron transfer (PCET) is key to the activation of the blue light using flavin (BLUF) domain photoreceptors. Here, to elucidate the photocycle of the central FMN-Gln-Tyr motif in the BLUF domain of OaPAC, we eliminated the intrinsic interfering W90 in the mutant design. We integrated the stretched exponential function into the target analysis to account for the dynamic heterogeneity arising from the active-site solvation relaxation and the flexible H-bonding network as shown in the molecular dynamics simulation results, facilitating a simplified expression of the kinetics model. We find that, in both the functional wild-type (WT) and the nonfunctional Q48E and Q48A, forward PCET happens in the range of 105 ps to 344 ps, with a kinetic isotope effect (KIE) measured to be ∼1.8 to 2.4, suggesting that the nature of the forward PCET is concerted. Remarkably, only WT proceeds with an ultrafast reverse PCET process (31 ps, KIE = 4.0), characterized by an inverted kinetics of the intermediate FMNH˙. Our results reveal that the reverse PCET is driven by proton transfer via an intervening imidic Gln.

Carbohydrate based biostimulation regulates the structure, function and remediation of Cr(VI) pollution by SRBs flora.

Sulfate reducing bacteria (SRBs) have promising applications as important microorganisms in the microbial approach to remediation of soil heavy metal pollution. However, fewer studies have been conducted on the differences in community structure, community function, heavy metal remediation capacity and effects with SRBs cultured from different carbohydrate. In this study, we investigated the structure and function of different SRBs flora, the reduction mechanism of Cr(VI) and remediation effect on Cr(VI) contaminated soil through high throughput sequencing, ICP-OES analysis and a series of soil remediation experiments. The results showed that there were significant differences in the community structure and function of SRBs flora cultured with different carbohydrate, and glycerine cultivated community with high SRBs abundance, diverse community structure, complete community function, which realizing the best SRBs flora performance. This SRBs flora under the optimal carbon/sulfur ratio, Fe(II), and sodium chloride conditions of 2, 50-500 mg/L, and 0-2.5 %, respectively and the highest sulfate and Cr(VI) reduction rates reached 84.2 % and 73.6 %, respectively, which the hydrogen sulfide pathway was the dominant pathway for Cr(VI) reduction. The SRBs flora cultured with glycerine, lactate, and butyrate obtained a good community structure sulfate and Cr(VI) reduction rates in contaminated soils, which the restored seed germination function and significantly blocked the migration of Cr(VI) into plants. The study provides new technical idea to regulate the structure and function of SRBs flora by means of selecting carbohydrate for the efficient remediation of soil Cr(VI) pollution.

Efficacy of photodynamic therapy in the treatment of oral candidiasis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the clinical efficacy of photodynamic therapy (PDT) as an adjunct or alternative to traditional antifungal drugs in the treatment of oral candidiasis, and to provide evidence-based medical evidence for its use in the treatment of oral candidiasis. METHODS: Computer combined with manual retrieval of China Academic Journals Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Science and Technology Journal Database (VIP), Wanfang Database, PubMed, Web of Science, Cochrane Library, Embase, Scopus retrieval for articles published before January 2023, basic information and required data were extracted according to the inclusion and exclusion criteria, and the Revman V5.4 software was used to conduct Meta-analysis of the included literature. RESULTS: A total of 11 articles were included, 7 of which used nystatin as an antifungal drug, 2 of which were combined treatment of PDT and nystatin, 2 of the remaining 4 articles were treated with fluconazole, and 2 were treated with miconazole. Meta results showed that PDT was superior to nystatin in reducing the number of oral candida colonies in the palate of patients MD = -0.87, 95%CI = (-1.52,-0.23), P = 0.008, the difference was statistically significant, and the denture site MD = -1.03, 95%CI = (-2.21, -0.15), P = 0.09, the difference was not statistically significant; compared with the efficacy of fluconazole, RR = 1.01, 95%CI = (0.56,1.83), P = 0.96; compared with miconazole RR = 0.55, 95%CI = (0.38, 0.81), P = 0.002; PDT combined with nystatin RR = 1.27, 95%CI = (1.06, 1.52), P = 0.01; recurrence rate RR = 0.28, 95%CI = (0.09, 0.88), P = 0.03. CONCLUSIONS: PDT was effective in the treatment of oral candidiasis; PDT was more effective than nystatin for the treatment of denture stomatitis in the palate, while there was no significant difference between the two for the denture site; The efficacy of PDT for oral candidiasis was similar to that of fluconazole; PDT was less effective than miconazole for oral candidiasis; Compared with nystatin alone, the combination of PDT and nystatin is more effective in treating oral candidiasis with less risk of recurrence.

Biodegradation characteristics and mechanism of quinoline by Ochrobactrum sp. strain C2.

A quinoline-degrading strain, C2, which could completely degrade 250 mg/L of quinoline within 24 h, was isolated from coking wastewater. Strain C2 was identified as Ochrobactrum sp. on the basis of 16S rDNA sequence analysis According to 16S rDNA gene sequence analysis, Strain C2 was identified as Ochrobactrum sp. Strain C2 could utilize quinoline as the sole carbon sources and nitrogen sources to grow and degrade quinoline well under acidic conditions. The optimum inoculum concentration, temperature and shaking speed for quinoline degradation were 10%, 30 °C and 150 r/min, respectively. The degradation of quinoline at low concentration by the strain followed the first-order kinetic model. The growth process of strain C2 was more consistent with the Haldane model than the Monod model, and the kinetic parameters were: Vmax = 0.08 h-1, Ks = 131.5 mg/L, Ki = 183.1 mg/L. Compared with suspended strains, strain C2 immobilized by sodium alginate had better degradation efficiency of quinoline and COD. The metabolic pathway of quinoline by Strain C2 was tentatively proposed, quinoline was firstly converted into 2(1H) quinolone, then the benzene ring was opened with the action of catechol 1,2-dioxygenase and subsequently transformed into benzaldehyde, 2-pentanone, hydroxyphenyl propionic acid and others.

Degradation of a Main Plastic Pollutant Polyethylene Terephthalate by Two Distinct Proteases (Neprilysin and Cutinase-like Enzyme).

In this DFT study, hydrolysis of polyethylene terephthalate (PET), a major cause of plastic pollution, by two distinct enzymes, neprilysin (NEP, a mononuclear metalloprotease) and cutinase-like enzyme (CLE, a serine protease), has been investigated. These enzymes utilize different mechanisms for the degradation of PET. NEP uses either the metal-bound hydroxide attack (MH) mechanism or reverse protonation (RP) mechanism, while CLE utilizes a general acid/base mechanism that includes acylation and deacylation processes. Additionally, the RP mechanism of NEP can proceed through three pathways, RP0, RP1, and RP2. The DFT calculations predict that, among all these mechanisms, the MH mechanism is the energetically most favorable one for the NEP enzyme. In comparison, CLE catalyzes this reaction with a significantly higher barrier. These results suggest that the Lewis acid and nucleophile activations provided by the Zn metal center of NEP are more effective than the hydrogen bonding interactions afforded by the catalytic Ser85-His180-Asp165 triad of CLE. They have provided intrinsic details regarding PET degradation and will pave the way for the design of efficient metal-based catalysts for this critical reaction.

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study.

In this study, mechanisms of hydrolysis of all four chemically diverse cleavage sites of human serum albumin (HSA) by [Zr(OH)(PW11 O39 )]4- (ZrK) have been investigated using the hybrid two-layer QM/MM (ONIOM) method. These reactions have been proposed to occur through the following two mechanisms: internal attack (IA) and water assisted (WA). In both mechanisms, the cleavage of the peptide bond in the Cys392-Glu393 site of HSA is predicted to occur in the rate-limiting step of the mechanism. With the barrier of 27.5 kcal/mol for the hydrolysis of this site, the IA mechanism is found to be energetically more favorable than the WA mechanism (barrier = 31.6 kcal/mol). The energetics for the IA mechanism are in line with the experimentally measured values for the cleavage of a wide range of dipeptides. These calculations also suggest an energetic preference (Cys392-Glu393, Ala257-Asp258, Lys313-Asp314, and Arg114-Leu115) for the hydrolysis of all four sites of HSA. © 2018 Wiley Periodicals, Inc.

Investigating coordination flexibility of glycerophosphodiesterase (GpdQ) through interactions with mono-, di-, and triphosphoester (NPP, BNPP, GPE, and paraoxon) substrates.

In this study, interactions of the catalytically active binuclear form of glycerophosphodiesterase (GpdQ) with four chemically diverse substrates, i.e. NPP (a phosphomonoester), BNPP and GPE (both phosphodiesters), and paraoxon (a phosphotriester) have been investigated using all-atom molecular dynamics (MD) simulations. The roles of metal ions and key amino acid residues, coordination flexibility, and dynamic transformations in all enzyme-substrate complexes have been elucidated. The roles of important first and second coordination shell residues in substrate binding and coordination flexibility of the enzyme suggested by simulations are supported by experimental data. The chemical nature of the substrate is found to influence the mode of binding, electrostatic surface potential, metal-metal distance, and reorganization of the active site. The experimentally proposed association between the substrate binding and coordination flexibility is analyzed using principal component analysis (PCA), movements of loops, and root-mean-square-fluctuations (RMSF) as parameters. The PCA of these substrates provides different energy basins, i.e. one, three, two and five for NPP, BNPP, GPE, and paraoxon, respectively. Additionally, the area of an irregular hexagon (268.3, 288.9, 350.8, and 362.5 Å2) formed by the residues on these loops illustrates their distinct motions. The substrate binding free energies of NPP, BNPP, and GPE are quite close (22.4-24.3 kcal mol-1), but paraoxon interacts with the smallest binding free energy (14.1 kcal mol-1). The metal binding energies in the presence of these substrates are substantially different, i.e. the lowest for NPP and the highest for paraoxon. These results thus provide deeper insight into the chemical promiscuity and coordination flexibility of this important enzyme.

Aggregate-Induced Self-Assembly and Ultrafast Dynamics of Light-Harvesting D-A-A Polymorphs.

Organic dipolar molecules are an emerging class of light harvesters useful in electronic applications and have captured new urgency with the design and synthesis of new molecular structures for device testing. However, research has not evolved beyond the cyclical thin film preparation-device testing-chemical structural modification approach. Without an understanding of polymorphism, molecular photophysics at the interface or metastable morphologies that regulate charge carrier dynamics, it is not obvious a priori if a new molecular structure will produce a suitable thin film morphology for superior device performance without developing structure-function relationships that consider morphology and photophysics. Dipolar, light harvesting molecules are synthesized with a covalent, para-functionalized triphenylamine donor (D) and acceptor (A) in π-conjugated structures, D-A1 and D-A1 -A2 , that have previously achieved 9.6% power conversion efficiency in thermally evaporated organic solar cell devices with C70 . Solution processing and morphological manipulation are hypothesized to reduce ultrafast radiative charge recombination, unique to dipolar structures, that prevents full charge separation to the fullerene. The photophysics of the D-A interface using femtosecond transient absorption spectroscopy is explained, and microscopy data reveal a newly discovered, supramolecular amorphous polymer metastable state presented as a transient absorption assisted strategy for photofunctional polymorph design.

Photoinduced charge recombination in dipolar D-A-A photonic liquid crystal polymorphs.

A hexylalkoxy dipolar D-A-A molecule [7-(4-N,N-(bis(4-hexyloxyphenyl)amino)phenyl)-2,1,3-(benzothia-diazol-4-yl)methylene]propane-dinitrile, (C6-TPA-BT-CN) has been synthesized and the photophysics studied via femtosecond transient absorption spectroscopy (FsTA) in toluene and in amorphous and liquid crystalline spherulite thin films. Two spherulite macromolecular crystalline phases (banded, and non-banded) were observed through concentration dependent, solution processing techniques and are birefringent with a negative sign of elongation. A dramatic change in the electronic absorption from blue in amorphous films to green in spherulites was observed, and the molecular orientation was determined through the combined analysis of polarized light microscopy, X-ray diffraction, and scanning electron microscopy. FsTA was performed on amorphous films and show complex charge recombination dynamics, and a Stark effect, characterized from the combined TPA+˙ and [BT-CN]-˙ spectroscopic signatures at 450 nm and 510 nm and identified through spectroelectrochemistry. Radical cation dynamics of TPA+˙ was observed selectively at 750 nm with >503.3 ps (18%) recombination kinetics resulting in a rather significant yield of free charge carriers in amorphous films and consistent with previous reports on energetically disordered blend films. However, photoexcitation on large, non-banded spherulites areas (>250 µm) reveal average monoexponential charge recombination lifetimes of 169.2 ps from delocalized states similar to those observed in amorphous films and are 5× longer-lived than previous reports [Chang et al., J. Am. Chem. Soc., 2013, 135, 8790] of a related methyl-DPAT-BT-CN whose amorphous thin films were prepared through vapor deposition. Thus, the correlation between the microstructure of the blend film and the photoinduced radical pair dynamics described here is critical for developing a fundamental understanding of how dipolar states contribute to the charge carrier yield in a disordered energy system.

Clinical efficacy and pain control of diode laser-assisted flap surgery in the treatment of chronic periodontitis:A systematic review and meta-analysis.

Objective: To assess the diode laser-assisted periodontal flap surgery's clinical effectiveness and postoperative pain management in treating chronic periodontitis, and to offer evidence-based medical justification for the procedure's clinical use. Data sources and study selection: In this study, a computer combined with manual search was used to search for articles on diode laser-assisted periodontal flap surgery for the treatment of chronic periodontitis published from the establishment of the database to September 2023. The databases searched included China Academic Journal Full Text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Science and Technology Journal Database (VIP), Wanfang Database, PubMed, Web of science, Cochrane Library, Embase, and Scopus. Two researchers independently performed the screening and study selection, following the inclusion and exclusion standards to extract basic information and required data. Meta-analysis of the included literature was performed using Revman V5.4 software. Result: Thirteen articles were analyzed. Meta-analysis showed that the use of the diode laser was effective in reducing patients' probing pocket depth (PPD) at 3 and 6 months postoperatively (3 months: MD = -0.46, 95 % CI = [-0.89, -0.03], P = 0.04; 6 months: MD = -0.35, 95 % CI = [-0.63, -0.06], P = 0.02), was able to effectively improve 3 month clinical attachment level (CAL) (MD = -0.36, 95 % CI = [-0.66, -0.06], P = 0.02), and was able to promote wound healing and reduce patients' early postoperative pain (MD = 0.67, 95 % CI = [0.01, 1.32], P = 0.05; MD = -1.67, 95 % CI = [-2.23, -1.00], and P < 0. 001), while for gingival index (GI), the use of diode laser did not have a significant effect. Conclusions: The available evidence suggests that the use of a diode laser adjunct is effective in reducing PPD, improving CAL, promoting wound healing, and reducing early postoperative pain in patients compared with flap application alone; however, for GI, diode lasers did not show any improvements. Clinical significance: Periodontal flap surgery fails to eliminate microorganisms from the soft tissue wall, potentially leading to recolonization, reinfection, and accompanying side effects such as pain and swelling. The use of a diode laser reduces PPD, improves CAL, and relieves early postoperative pain.

Photoactivated disinfection procedure for denture stomatitis in diabetic rats.

Objective: To study the efficacy of PADTM Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model. Methods: The diabetic rat DS model was developed by randomly selecting 2-month-old male Sprague-Dawley rats and dividing them into four groups. The palate and denture surfaces of rats in the PAD groups were incubated with 1 mg/mL toluidine blue O for 1 min each, followed by a 1-min exposure to 750-mW light-emitting diode light. The PAD-1 group received one radiation treatment, and the PAD-2 group received three radiation treatments over 5 days with a 1-day interval. The nystatin (NYS) group received treatment for 5 days with a suspension of NYS of 100,000 IU. The infection group did not receive any treatment. In each group, assessments included an inflammation score of the palate, tests for fungal load, histological evaluation, and immunohistochemical detection of interleukin-17 (IL-17) and tumor necrosis factor (TNF-α) conducted 1 and 7 days following the conclusion of treatment. Results: One day after treatment, the fungal load on the palate and dentures, as well as the mean optical density values of IL-17 and TNF-α, were found to be greater in the infection group than in the other three treatment groups (P < 0.05). On the 7th day after treatment, these values were significantly higher in the infection group than in the PAD-2 and NYS groups (P < 0.05). Importantly, there were no differences between the infection and PAD-1 groups nor between the PAD-2 and NYS groups (P > 0.05). Conclusions: PAD effectively reduced the fungal load and the expressions of IL-17 and TNF-α in the palate and denture of diabetic DS rats. The efficacy of multiple-light treatments was superior to that of single-light treatments and similar to that of NYS.

Lithium Niobate MEMS Antisymmetric Lamb Wave Resonators with Support Structures.

The piezoelectric thin film composed of single-crystal lithium niobate (LiNbO3) exhibits a remarkably high electromechanical coupling coefficient and minimal intrinsic losses, making it an optimal material for fabricating bulk acoustic wave resonators. However, contemporary first-order antisymmetric (A1) Lamb mode resonators based on LiNbO3 thin films face specific challenges, such as inadequate mechanical stability, limited power capacity, and the presence of multiple spurious modes, which restrict their applicability in a broader context. In this paper, we present an innovative design for A1 Lamb mode resonators that incorporates a support-pillar structure. Integration of support pillars enables the dissipation of spurious wave energy to the substrate, effectively mitigating unwanted spurious modes. Additionally, this novel approach involves anchoring the piezoelectric thin film to a supportive framework, consequently enhancing mechanical stability while simultaneously improving the heat dissipation capabilities of the core.

Improvement of DC Performance and RF Characteristics in GaN-Based HEMTs Using SiNx Stress-Engineering Technique.

In this work, the DC performance and RF characteristics of GaN-based high-electron-mobility transistors (HEMTs) using the SiNx stress-engineered technique were systematically investigated. It was observed that a significant reduction in the peak electric field and an increase in the effective barrier thickness in the devices with compressive SiNx passivation contributed to the suppression of Fowler-Nordheim (FN) tunneling. As a result, the gate leakage decreased by more than an order of magnitude, and the breakdown voltage (BV) increased from 44 V to 84 V. Moreover, benefiting from enhanced gate control capability, the devices with compressive stress SiNx passivation showed improved peak transconductance from 315 mS/mm to 366 mS/mm, along with a higher cutoff frequency (ft) and maximum oscillation frequency (fmax) of 21.15 GHz and 35.66 GHz, respectively. Due to its enhanced frequency performance and improved pinch-off characteristics, the power performance of the devices with compressive stress SiNx passivation was markedly superior to that of the devices with stress-free SiNx passivation. These results confirm the substantial potential of the SiNx stress-engineered technique for high-frequency and high-output power applications, which are crucial for future communication systems.

Topical Chinese herbal compound in the treatment of oral candidiasis: A systematic review and meta-analysis of randomized controlled trials.

Objective: A meta-analysis was performed to systematically review the clinical efficacy of external traditional Chinese medicine compounds in the treatment of oral candidiasis to provide a reference for the clinical treatment of this disease. Methods: We systematically searched relevant Chinese and English databases, including the Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, PubMed, Web of Science, the Cochrane Library and Scopus, from inception to September 2022 to identify all clinical randomized controlled studies of oral candidiasis treated with external Chinese medicine compounds. The inclusion criteria were a randomized controlled study of an experimental group with the intervention of an external traditional Chinese medicine compound, and the results of the literature were clear. Duplicate publications, literature on single or proprietary Chinese medicine treatment, literature from which relevant data could not be extracted and studies without rigorous experimental designs were excluded. Two researchers independently screened relevant studies that met the inclusion and exclusion criteria and conducted quality evaluation and data extraction for the included studies. The total effective rate, Candida negative conversion rate and recurrence rate were statistically analysed by RevMan 5.3 software. Results: This study included 29 studies and 30 studies, involving 2553 patients with oral candidiasis, with 1320 in the experimental group and 1233 in the control group. The total effective rate of the experimental group was better than that of the control group (RR = 1.21 [1.15, 1.27], P < 0.000). The negative rate of Candida in the experimental group was better than that in the control group (RR = 1.25 [1.05, 1.50], P=0.01). The recurrence rate of the experimental group was lower than that of the control group (RR = 0.34 [0.18, 0.63], P=0.0007). The difference was statistically significant. Conclusion: Compared with Western medicine alone, external traditional Chinese medicine in the treatment of oral candidiasis has certain advantages in improving the total effective rate, increasing the negative conversion rate of Candida and reducing the recurrence rate. However, larger samples and high-quality clinical studies are needed to obtain further support and verification.

Rapid Inactivation of mixed biofilms of Candida albicans and Candida tropicalis using antibacterial photodynamic therapy: Based on PAD™ Plus.

Background: To investigate the sterilizing effect of antimicrobial photodynamic therapy (aPDT) based on PAD™ Plus on mixed biofilms of Candida albicans and Candida tropicalis. Methods: A mature mixed biofilm model of C. albicans and C. tropicalis was constructed in vitro. FITC-concanavalin A staining was conducted to observe the formation of the extracellular matrix. MTT assay was performed to determine biofilm viability. The chromogenic medium was used to examine the Candida composition of the mixed biofilms. For aPDT treatment, based on PAD™ Plus, the biofilms were incubated with 1 mg/mL TBO for 1, 5, or 10 min, followed by 500 or 750 mW LED illumination for 1 or 2 min. The live/dead fungi were detected by SYTO9/propidium iodide staining. A multivariate factorial design was conducted to analyze the correlations of parameters with the inactivation effect of the mixed biofilms. Results: Mature mixed biofilms formed at 24 h after seeding. Compared with untreated biofilms, following 1-min TBO incubation, 500 mW LED illumination for 1 min inactivated more than 90% of the fungi. Extending the incubation time did not significantly improve the inactivation effect. Application of 750 mW output power or 2 min LED illumination inactivated more than 99% of the fungi without increasing other parameters. Conclusions: PAD™ Plus combined with 1 mg/mL TBO can rapidly inactivate the mature mixed biofilms of C. albicans and C. tropicalis, serving as a robust platform for the treatment of mixed infections of C. albicans and C. tropicalis.

The relationship between leptin and periodontitis: a literature review.

Leptin is a peptide hormone that regulates energy balance, immune inflammatory response, and bone metabolism. Several studies have demonstrated a relationship between leptin and periodontitis, a local inflammatory disease that progressively weakens the supporting structures of the teeth, eventually leading to tooth loss. This article reviews the existing literature and discusses leptin's basic characteristics, its relationship with periodontitis, and its effects on periodontal tissue metabolism.

Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2.

The 3C-like protease (3CLpro) is essential for the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it a promising target for the treatment of corona virus disease 2019 (COVID-19). In this study, a series of 2,3,5-substituted [1,2,4]-thiadiazole analogs were discovered to be able to inhibit 3CLpro as non-peptidomimetic covalent binders at submicromolar levels, with IC50 values ranging from 0.118 to 0.582 µM. Interestingly, these compounds were also shown to inhibit PLpro with the same level of IC50 values, but had negligible effect on proteases such as chymotrypsin, cathepsin B, and cathepsin L. Subsequently, the antiviral abilities of these compounds were evaluated in cell-based assays, and compound 6g showed potent antiviral activity with an EC50 value of 7.249 µM. It was proposed that these compounds covalently bind to the catalytic cysteine 145 via a ring-opening metathesis reaction mechanism. To understand this covalent-binding reaction, we chose compound 6a, one of the identified hit compounds, as a representative to investigate the reaction mechanism in detail by combing several computational predictions and experimental validation. The process of ring-opening metathesis was theoretically studied using quantum chemistry calculations according to the transition state theory. Our study revealed that the 2,3,5-substituted [1,2,4]-thiadiazole group could covalently modify the catalytic cysteine in the binding pocket of 3CLpro as a potential warhead. Moreover, 6a was a known GPCR modulator, and our study is also a successful computational method-based drug-repurposing study.

Macrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery.

Interest in macrocycles as potential therapeutic agents has increased rapidly. Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds, which can contribute to the improvement of the biological activity and physicochemical properties of these molecules. In this study, we propose a computational macrocyclization method based on Transformer architecture (which we name Macformer). Leveraging deep learning, Macformer explores the vast chemical space of macrocyclic analogues of a given acyclic molecule by adding diverse linkers compatible with the acyclic molecule. Macformer can efficiently learn the implicit relationships between acyclic and macrocyclic structures represented as SMILES strings and generate plenty of macrocycles with chemical diversity and structural novelty. In data augmentation scenarios using both internal ChEMBL and external ZINC test datasets, Macformer display excellent performance and generalisability. We showcase the utility of Macformer when combined with molecular docking simulations and wet lab based experimental validation, by applying it to the prospective design of macrocyclic JAK2 inhibitors.

DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs.

The rational design of PROTACs is difficult due to their obscure structure-activity relationship. This study introduces a deep neural network model - DeepPROTACs to help design potent PROTACs molecules. It can predict the degradation capacity of a proposed PROTAC molecule based on structures of given target protein and E3 ligase. The experimental dataset is mainly collected from PROTAC-DB and appropriately labeled according to the DC50 and Dmax values. In the model of DeepPROTACs, the ligands as well as the ligand binding pockets are generated and represented with graphs and fed into Graph Convolutional Networks for feature extraction. While SMILES representations of linkers are fed into a Bidirectional Long Short-Term Memory layer to generate the features. Experiments show that DeepPROTACs model achieves 77.95% average prediction accuracy and 0.8470 area under receiver operating characteristic curve on the test set. DeepPROTACs is available online at a web server ( https://bailab.siais.shanghaitech.edu.cn/services/deepprotacs/ ) and at github ( https://github.com/fenglei104/DeepPROTACs ).