Optimal Binding Research Articles

First molecules to reactivate RASG12V GTPase activity

BackgroundSmall-molecule compounds that even partially restore the GTPase activity of RASG12V can be used in anticancer therapy. Until now, attempts to obtain such compounds have failed. Compounds with this ability have been defined in our research.MethodsThe compounds were initially identified through virtual screening, and their optimal binding conformation in the RAS SW-II pocket was determined using the flexible docking technique. Efficacy was verified based on the IC50 determination, GTPase activity, as well as the AKT and ERK phospho WB assays.ResultsThe IC50 of the tested compounds was significantly lower against cells with the RASG12V mutation than against selected types of normal cells. The molecular mechanism of action of these compounds was proposed – minimization of the negative impact of the V12 sidechain on GTP hydrolysis of RASG12V. The work also indicates that the model of action of RAS mutants in cell lines is incomplete. The analysed cell line (SW-480) with RAS mutations does not always show increased ERK and AKT activity.ConclusionsWe have demonstrated molecules that partially restore the GTPase activity of RASG12V. Their mechanism of action is well explained based on current RAS mutant conformation and mechanistic models. These molecules inhibit the RAS-AKT pathway and show higher cytotoxicity against cancer cells with the RASG12V mutation (SW-480 cell line). However, SW-480 cells can switch into the subline proliferating independently of AKT phosphorylation and show partial resistance to the molecules described in this article.

Deciphering the Origin of Higher Shell Coordination on Single Iron Catalysts for Resilient Modulating Persulfate Oxidation Into Singlet Oxygen Pathway

AbstractPrecise manipulation of coordination structure of single‐atom sites and establishment of schematic microenvironment‐oxidation pathway relations remain significant challenges in Fenton‐like chemistry. Herein, incorporating sulfur heteroatoms into the higher coordination shell of FeN4 structure (Fe‐NSC) exhibited a volcano trend of p‐hydroxybenzoic acid oxidation, aligning with the number and positions of sulfur dopant. Specifically, higher shell S coordination with moderate electronegativity and larger atomic radii triggers long‐range electronic interactions, which provoke Fe 3d orbital splitting and spin electron rearrangement, resulting in a spin crossover with orbital states dxy2 dyz1 dxz2 dz21. As a result, the partial filling of eg and t2 g orbitals and moderate σ/π antibonding states between 3d and 2p atomic states optimized the adsorption–desorption behaviors of the key oxygenated intermediates from peroxymonosulfate activation. Thus, the optimal binding configuration weakens the Fe─O bonding and accelerates PMS dissociation to yield C‐S‐N4Fe‐O*, which subsequently couples to form 1O2 with nearly 100% selectivity. The Fe‐NSC‐functionalized membrane exhibited outstanding long‐term reusability in a continuous flow reactor which further validated practical application perspective. This study provides insight at both atomic and electronic levels for rational design of spin‐polarized catalysts and its functions in fine‐tuning oxidation pathways in environmental catalysis.

RNA recognition by minimal ProQ from Neisseria meningitidis.

Neisseria meningitidis minimal ProQ is a global RNA binding protein belonging to the family of FinO-domain proteins. The N. meningitidis ProQ consists only of the FinO domain accompanied by short N- and C-terminal extensions. To better understand how this minimal FinO-domain protein recognizes RNAs, we compared its binding to seven different natural RNA ligands of this protein. Next, two of these RNAs, rpmG-3' and AniS, were subject to further mutational studies. The data showed that N. meningitidis ProQ binds the lower part of the intrinsic transcription terminator hairpin, and that the single-stranded sequences on the 5' and 3' side of terminator stem are required for tight binding. However, the specific lengths of 5' and 3' RNA sequences required for optimal binding differed between the two RNAs. Additionally, our data show that the 2'-OH and 3'-OH groups of the 3' terminal ribose contribute to RNA binding by N. meningitidis ProQ. In summary, the minimal ProQ protein from N. meningitidis has generally similar requirements for RNA binding as the isolated FinO domains of other proteins of this family, but differs from them in detailed RNA features that are optimal for specific RNA recognition.

From non-affinity to high-affinity: Rapid preparation of nanobodies utilizing high-precision alphafold and structural-interaction analysis for detection of enrofloxacin in marine fish.

Traditional antibody preparation methods rely on animal immunization and experimental screening, often requiring 3-6 months, which cannot meet the urgent demands for antibodies in environmental emergencies or contamination events. Herein, a rapid antibody preparation method was proposed to transform anti-macromolecule nanobodies into high-affinity anti-small molecule (enrofloxacin) nanobodies, based on the high-precision predictive capabilities of AlphaFold, integrated with structural and interaction analysis. The high-precision prediction capability of AlphaFold ensured the accuracy of nanobody structural analysis and targeted modification. Binding structure design enabled the antigen and antibody to adopt an optimal binding conformation. Interaction analysis provided guidance for targeted modifications and served as a tool for evaluating the results. Molecular docking results revealed that the template nanobodies, which initially couldn't dock with enrofloxacin, formed 3-5 noncovalent bonds after modification. Bio-layer interferometry (BLI) assays demonstrated that the equilibrium dissociation constant (KD) of the modified nanobodies ranged from 5.56 ± 0.34 nM to 94.73 ± 4.35 nM, with half-maximal inhibitory concentration (IC50) between 231.9 and 3293.6 ng/mL. Based on the modified nanobodies and BLI platform, the detection of enrofloxacin in marine fish was achieved with a limit of detection (LOD) as low as 59.97 μg/kg. In summary, this study provided a novel perspective for the rapid nanobody preparation, showing significant potential in food safety and environmental monitoring.

Electrostatic and Electronic Effects on Doped Nickel Oxide Nanofilms for Water Oxidation.

An ideal water-splitting electrocatalyst is inexpensive, abundant, highly active, stable, selective, and durable. The anodic oxygen evolution reaction (OER) is the main bottleneck for H2 production with a complex and not fully resolved mechanism, slow kinetics, and high overpotential. Nickel oxide-based catalysts (NiOx) are highly active and cheaper than precious metal catalysts. However, rigorous catalyst tests and DFT calculations are still needed to rationally optimize NiOx catalysts. In this work, we combine plasma-enhanced atomic layer deposition (PE-ALD) and density functional theory (DFT) to address the role of dopants in promoting NiOx OER activity. Ultrathin films of NiOx doped with Zn2+, Al3+, and Sn4+ presented improved intrinsic activity, stability, and durability for the OER. The results show a low to high catalytic performance of ZnNiOx < NiOx < AlNiOx < SnNiOx, which we attribute to an increase in the concentration of valence band (VB) holes combined with conduction band (CB) electron conductivity, characterized by electrochemical impedance spectroscopy (EIS). The influence of doping on the electronic structure and catalytic activity was investigated using advanced characterization techniques and density functional theory (DFT) calculations (PEB0/pob-TZVP). DFT complements the experimental results, showing that the dopant charge states and orbital hybridization enhance the OER by improving the charge carrier concentration and mobility, thus allowing optimal binding energies and charge dynamics and delocalization. Our findings demonstrate the potential of PE-ALD-doped nanofilms NiOx and DFT to rationally design and develop catalysts for sustainable energy applications.

Beyond Current Frontiers of Electrocatalysis

One of the key reasons why the transition to renewable energy sources is progressing slowly is the low efficiency of processes at electrified interfaces where electricity is converted and stored as chemical energy. The challenge behind low efficiency is sluggish electrochemical conversion reactions. To resolve low efficiency, it is necessary to comprehend the intrinsic reasons behind the unusually complex phenomena of converting electrical energy into chemical energy, and vice versa, chemical energy into electrical energy. An important example is the electrolysis of water, where, after decades of research, it is not clear how to significantly accelerate the processes of hydrogen and oxygen generation. Of critical importance for the control of the water electrolysis mechanism is understanding the origins of the electrocatalytic activity. If we ask a key question from a conceptual point of view, namely: what are the origins of electrocatalytic activity? The answer will be, in most cases, as it was 70 years ago. Namely, the paradigm of electrocatalysis is the Sabatier principle, which suggests optimal ("not too strong, not too weak") binding of intermediates as the main prerequisite for a high reaction rate. Conventional wisdom suggests that confirmation of this should be a linear relationship between the adsorption energy of the intermediate and the activation energy, known as the Brønsted-Evans-Polanyi relation. However, recent results show that lowering the activation energy is not necessarily beneficial for increasing the reaction rate. In this work, some fundamentally important questions about the nature of electrocatalytic activity will be raised. Identifying and analyzing these issues can be an important trigger and driver towards efficient water electrolysis and a more comprehensive understanding of electrocatalysis as a scientific field of key importance for the conversion, storage and utilization of energy from renewable sources.

Normalized Protein-Ligand Distance Likelihood Score for End-to-End Blind Docking and Virtual Screening.

Molecular Docking is a critical task in structure-based virtual screening. Recent advancements have showcased the efficacy of diffusion-based generative models for blind docking tasks. However, these models do not inherently estimate protein-ligand binding strength thus cannot be directly applied to virtual screening tasks. Protein-ligand scoring functions serve as fast and approximate computational methods to evaluate the binding strength between the protein and ligand. In this work, we introduce normalized mixture density network (NMDN) score, a deep learning (DL)-based scoring function learning the probability density distribution of distances between protein residues and ligand atoms. The NMDN score addresses limitations observed in existing DL scoring functions and performs robustly in both pose selection and virtual screening tasks. Additionally, we incorporate an interaction module to predict the experimental binding affinity score to fully utilize the learned protein and ligand representations. Finally, we present an end-to-end blind docking and virtual screening protocol named DiffDock-NMDN. For each protein-ligand pair, we employ DiffDock to sample multiple poses, followed by utilizing the NMDN score to select the optimal binding pose, and estimating the binding affinity using scoring functions. Our protocol achieves an average enrichment factor of 4.96 on the LIT-PCBA data set, proving effective in real-world drug discovery scenarios where binder information is limited. This work not only presents a robust DL-based scoring function with superior pose selection and virtual screening capabilities but also offers a blind docking protocol and benchmarks to guide future scoring function development.

The Impact of Selenium on the Physiological Activity of Yeast Cells Saccharomyces cerevisiae ATCC 7090 and Rhodotorula glutinis CCY 20-2-26.

This study investigated the selenium-binding capacity of the biomass of two yeast strains, Saccharomyces cerevisiae American Type Culture Collection (ATCC) 7090 and Rhodotorula glutinis CCY 20-2-26. The studies carried out methods of bioaccumulation by yeast biomass. Inorganic selenium was added to the culture media as an aqueous solution of Na2SeO3 at concentrations ranging from 0 to 40 mg Se4+/L. The addition of selenium at concentrations >0.5 mg/L significantly reduced biomass yield compared with the control in the case of S. cerevisiae. A significant reduction in the biomass of R. glutinis was observed only at selenium doses >30 mg/L. The study found that for S. cerevisiae, cultivation should occur for 24 h in a medium with an initial selenium concentration of 20 mg/L to achieve the most efficient selenium accumulation by the yeast biomass. Under these conditions, the yeast could accumulate 4.27 mg Se4+/g. For the red yeast R. glutinis, optimal selenium binding conditions were achieved by cultivating for 48 h in a medium with an initial selenium ion concentration of 40 mg/L. This yeast strain was more resistant to high selenium doses, accumulating 7.53 mg Se4+/L at the highest tested dose (40 mg Se4+/L). Selenium supplementation of the medium from 20 mg Se4+/L and cultivation for 72 h caused significant changes in the morphology of S. cerevisiae cells (e.g., increased surface area compared with the control). Selenium doses of 20-40 mg/L after 48 h of cultivation significantly reduced the surface area compared with the control results for R. glutinis cells. Selenium significantly impacted carotenoid pigment production, with levels decreasing as the selenium concentration in the medium increased. Furthermore, selenium in the tested concentration range increased protein content in the cellular biomass but did not affect intracellular lipid production.

Synthesis and Pharmacology of Clinical Drugs Containing Isoindoline Heterocycle Core

Heterocyclic compounds are the cornerstone for active pharmaceutical ingredients. Among heterocycles, isoindoline core occupies a special place, as ten commercial bioactive compounds/drugs contain this skeleton decorated with several functional groups required for optimal receptor binding. These drugs are employed for indications such as multiple myeloma, leukemia, inflammation, hypertension, edema, obesity, and insect control. This review presents the pharmacological activities, mechanisms of action, and chemical syntheses of these commercial bioactive molecules/drugs.

Molecular Mechanisms of Magnolol in Gastric Precancerous Lesions: A Computational and Experimental Study.

The formation of gastric precancerous-lesions(GPLs) has been identified as a critical step intumorigenesis, and patients with GPLs have an increased risk of gastric cancer. Magnolol is the primary biphenolic compound inMagnolia officinalis. It possesses variouspharmacological properties, such ascardioprotective and neuroprotective properties, and inhibit tumor growth. However, its therapeutic effects on GPLstreatment and the related mechanisms have not yet been studied. To address this, the mechanisms by whichmagnolol affectsGPLswere elucidated via protein-chemical interaction predictionanalysis, molecular docking, molecular dynamics simulation, and experimental verification. GPL-related targets were obtained from the GeneCards database, whereasmagnolol targets were obtained from the STITCHdatabase. The two group of targets were compared by constructing a Venn diagram, and potential key GPL-related targets of magnolol were identified. Next, the interactions between the active compounds of magnololand epithelial-mesenchymal transition (EMT)-related proteins were evaluated via molecular docking. The protein-compound complexes with the optimal binding affinity were analysed viamolecular dynamics simulation. The efficacy and mechanismsof Magnolol in the treatment of GPLs werefurther assessed using in-vitro models. Magnolol exerts its pharmacological effects by acting on multiple targets. ERBB2 might be a potential target of magnolol in GPL treatment.

Exploiting Lattice Carbon-Induced Modulation Effect in Nickel towards Efficient Alkaline Hydrogen Oxidation.

Doping with non-metallic heteroatom is an effective approach to tailor the electronic structure of Ni for enhancing its alkaline hydrogen oxidation reaction (HOR) catalytic performance. However, the modulation of HOR activity of Ni by lattice carbon (LC) atoms has rarely been reported, especially to reveal the rule between the doping effect and activity caused by the content of LC atoms. Here, hydrogen is proposed as a scavenger for LC atoms in the pyrolytic reduction process to finely control the content of LC atoms in Ni. With the removal of LC atoms in Ni lattice, the electronic structure changes from Ni3C-like electronic structure to quasi-Ni structure. Furthermore, a volcanic relationship between the LC content and HOR activity of Ni is established for the first time. The Cless-Ni (LC0.44-Ni) with optimized LC content shows the best activity owing to the weakened hydrogen binding energy (HBE) and optimal hydroxyl binding energy (OHBE). This work provides an inspiration for the design of high-performance catalysts by tailoring the electronic structure of the metal via LC atoms doping.

Exploiting Lattice Carbon‐Induced Modulation Effect in Nickel towards Efficient Alkaline Hydrogen Oxidation

Doping with non‐metallic heteroatom is an effective approach to tailor the electronic structure of Ni for enhancing its alkaline hydrogen oxidation reaction (HOR) catalytic performance. However, the modulation of HOR activity of Ni by lattice carbon (LC) atoms has rarely been reported, especially to reveal the rule between the doping effect and activity caused by the content of LC atoms. Here, hydrogen is proposed as a scavenger for LC atoms in the pyrolytic reduction process to finely control the content of LC atoms in Ni. With the removal of LC atoms in Ni lattice, the electronic structure changes from Ni3C‐like electronic structure to quasi‐Ni structure. Furthermore, a volcanic relationship between the LC content and HOR activity of Ni is established for the first time. The Cless‐Ni (LC0.44‐Ni) with optimized LC content shows the best activity owing to the weakened hydrogen binding energy (HBE) and optimal hydroxyl binding energy (OHBE). This work provides an inspiration for the design of high‐performance catalysts by tailoring the electronic structure of the metal via LC atoms doping.

Selective Mu-Opioid Receptor Imaging Using 18F-Labeled Carfentanils.

Carfentanil, a highly potent synthetic opioid, paradoxically serves as a crucial positron emission tomography (PET) imaging tool in neurobiological studies of the mu-opioid receptor (MOR) system when labeled with carbon-11 ([11C]CFN). However, its clinical research use is hindered by extreme potency and the limited availability of short-lived carbon-11 (t1/2 = 20.4 min). We present fluorine-18-labeled fluorocarfentanils ([18F]FCFNs), which can be produced at higher molar activity, allowing for lower mass doses and benefiting from the longer half-life of fluorine-18 (t1/2 = 109.8 min), facilitating broader accessibility. Using copper-mediated radiofluorination, we synthesized a small [18F]FCFN library and conducted preclinical imaging evaluations. Two candidates, o-18F-1 and p-18F-2, showed optimal brain uptake, favorable pharmacokinetics, and high MOR-specific binding. Selectivity was confirmed through in vitro binding assays and in vivo PET scans. These [18F]FCFNs are promising for accessible human brain MOR imaging.

The olfactory recognition between leaf-cutter bee Megachile saussurei and alfalfa floral volatiles mediated by odorant binding protein 4 (MsauOBP4).

Megachile saussurei (Hymenoptera, Megachilidae) is a primary insect pollinator of alfalfa (Medicago sativa L.) in northwestern China. However, the mechanisms underlying the olfactory responses of M. saussurei induced by alfalfa volatiles is still unclear. Here, the interaction between MsauOBP4 and alfalfa floral volatiles was first elucidated. Results suggested that thirty-two alfalfa floral volatiles were identified and MsauOBP4 was successfully expressed with the consistent molecular mass as predicted results. MsauOBP4 displayed a broad binding spectrum to 32 volatiles, among which MsauOBP4 showed the strongest binding ability to (Z)-3-Hexen-1-ol. In the Y-tube olfactometer behavioral bioassay, M. saussurei elicited the most significant behavioral preference (Z)-3-Hexen-1-ol. MsauOBP4 showed an optimal binding feature to (Z)-3-Hexen-1-ol and valine was the key residue in binding the ligands. After silencing the MsauOBP4, the preference and EAG values of M. saussurei to (Z)-3-Hexen-1-ol were significantly decreased and selection rate of M. saussurei to alfalfa flowers dropped to 57.50% from 83.33%. These findings indicated that (Z)-3-Hexen-1-ol is a crucial component in the host location process mediated by MsauOBP4.

Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an SN2 reaction, followed by modifications at the C2- and N6-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N6-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ Ki=2.8μM, PPARδ Ki=43nM). This compound significantly enhanced adiponectin production and promoted adipogenic differentiation in hBM-MSCs. The 4'-seleno substitution preserved ligand functionality while enhancing binding affinity and pharmacological efficacy. In silico docking studies supported these binding affinities, demonstrating optimal binding poses for 3h at both PPARγ and PPARδ. These findings underscore the potential of 4'-selenonucleosides as therapeutic agents for metabolic disorders associated with hypoadiponectinemia, meriting further investigation and clinical development.

Cytotoxicity and molecular docking analysis of phytochemicals from Vallisneria spiralis with protein target 3CZH in breast cancer management

The anticancer potential of Vallisneria spiralis Linnaeus (Vallisneria spiralis L.) for human breast cancer management is of interest. In vitro shows that increasing concentrations of Vallisneria spiralis silver nanoparticles (AgNPs) and iron oxide nanoparticles (IONPs) resulted in greater cytotoxicity against MCF-7 breast cancer cells. The antioxidant potential of Vallisneria spiralis L. was assessed using 2-diphenyl-1-picryl-hydroxyl (DPPH) radical scavenging assay. Further molecular docking analysis of phytocompounds from Vallisneria spiralis L. with the target protein (PDB ID: 3CZH) shows optimal binding features. Thus, cytotoxicity analysis of Vallisneria spiralis for breast cancer with molecular docking of its phytochemicals and a target protein 3CZH is reported for further consideration.

An in-silico study of FIKK9.5 protein of Plasmodium falciparum for identification of therapeutics

The FIKK protein family, encompassing 21 serine-threonine protein kinases, is a distinctive cluster exclusive to the Apicomplexa phylum. Predominantly located in Plasmodium falciparum which is a malarial parasite, with a solitary gene identified in a distinct apicomplexan species, this family derives its nomenclature from - phenylalanine, isoleucine, lysine, lysine (FIKK), a conserved amino acid motif. Integral to the parasite’s life cycle and consequential to malaria pathogenesis, the absence of orthologous proteins in eukaryotic organisms designates it as a promising antimalarial drug target. Among the FIKKs, FIKK9.5 plays a pivotal role in the parasite’s development within red blood cells (RBCs). This investigation acquired the three-dimensional structure of FIKK9.5 and its ligands through extensive database searches and literature review. Computational screening of natural phytochemicals derived from plants traditionally used in antimalarial remedies was conducted by employing the Glide docking suite. AutoDock Vina was utilized to discern the inhibitor exhibiting optimal binding affinity. Subsequently, Molecular Dynamics (MD) simulations employing GROMACS validated Rufigallol as the most potent inhibitory compound against FIKK9.5. The robustness of the protein-ligand complex was scrutinized through a 200 nanosecond molecular dynamics (MD) trajectory. Trajectory analysis and determination of binding free energies were accomplished using MM-GBSA and MM-PBSA approaches. The ligand-binding exhibited sustained stability throughout the simulation, manifesting an approximate binding free energy of −25.5986 kcal/mol. This comprehensive computational study lays the groundwork for potential experimental validation in the laboratory, paving the way for the development of novel therapeutics targeting FIKK9.5 in the pursuit of innovative antimalarial.

Potential candidates from a functional food Zanthoxyli Pericarpium (Sichuan pepper) for the management of hyperuricemia: high-through virtual screening, network pharmacology and dynamics simulations.

Hyperuricemia (HUA) is a metabolic syndrome caused by purine metabolism disorders. Zanthoxyli Pericarpium (ZP) is a medicinal and food homologous plant, and its ripe peel is used to treat diseases and as a spice for cooking. Some studies have shown that ZP can inhibit the formation of xanthine oxidase and reduce the production of uric acid. Through network pharmacology, ZP's potential targets and mechanisms for HUA treatment were identified. Databases like TCMSP, UniProt, and Swiss Target Prediction were utilized for ZP's active ingredients and targets. HUA-related targets were filtered using GeneCards, Drugbank, and Open Targets. Core targets for ZP's HUA treatment were mapped in a PPI network and analyzed with Cytoscape. GO and KEGG pathway enrichments were conducted on intersected targets via DAVID. Molecular docking and virtual screening were performed to find optimal binding pockets, and ADMET screening assessed compound safety. Molecular dynamics simulations confirmed compound stability in binding sites. We identified 81 ZP active ingredient targets, 140 HUA-related targets, and 6 drug targets, with xanthine dehydrogenase (XDH) as the top core target. Molecular docking revealed ZP's active ingredients had strong binding to XDH. Virtual screening via Protein plus identified 48 compounds near the optimal binding pocket, with 2'-methylacetophenone, ledol, beta-sitosterol, and ethyl geranate as the most promising. Molecular dynamics simulations confirmed binding stability, suggesting ZP's potential in HUA prevention and the need for further experimental validation. Our study provides foundations for exploring the mechanism of the lowering of uric acid by ZP and developing new products of ZP. The role of ZP in the diet may provide a new dietary strategy for the prevention of HUA, and more experimental studies are needed to confirm our results in the future.

In-Situ Desalination-Coupled Electrolysis with a Membrane Stack System Producing Value-Added Chemicals

An efficient multi-functional electrolyzer with an electrodeposited Ni- and Fe-layered double hydroxide (NiFe-LDH) anode and an electrodeposited NiMo cathode is designed for overall water splitting coupled with the desalination of saline water and production of acid and base solution. NiFe-LDH is characterized by abundant active sites for OH adsorption and an optimal binding energy for M-OH. Meanwhile, loading bimetallic NiMo on an active electrode for the HER has been known to improve the electrocatalytic activity and durability owing to its high surface area. The NiFe-LDH and NiMo pairs separated by a bipolar membrane (BPM) show overpotentials as low as those of noble metal catalysts for oxygen and hydrogen evolution reactions in 1 M KOH and 1 M H2SO4 solutions, respectively. Thereafter, the electrode pair with an array of anion- and cation-exchange membranes (AEMs and CEMs) in alternatively stacking manner showed the desalination of brackish water and seawater at specific energy consumption of 1.8 kW h m−3, with concurrent production of HCl and NaOH. The Faradaic efficiencies of the device for O2 and H2 production are >95% at J = 100 mA cm−2 over 20 h, while the initial pH values of the anolyte and catholyte remain unchanged. The proposed multi-functional electrolyzer is highly promising for converting electrical energy into hydrogen energy, simultaneously desalinating saline water, and producing value-added chemicals. Subsequently, we compared electrodialytic performance over unit cell thickness, types of ion exchange membranes, and number of stacks in the device.This work is financially supported by Korea Water Cluster (KWC) as Korea Water Cluster ProjectLab. This work was supported by the Technology Innovation Program (or Industrial Strategic Technology Development Program-Alchemist Project) (NTIS-1415187362, 20025773, Development of building-Integrated Carbon Control Technologies) funded By the Ministry of Trade, Industry & Energy(MOTIE, Korea).

Molecular dynamic simulations to explore the broad-spectrum activity of the inhibitor PF-07321332 against human coronavirus

The main protease (Mpro) stands as a pivotal enzyme crucial for coronavirus replication, thus serving as a prime target for coronavirus drug discovery endeavors. Nirmatrelvir (PF-07321332), an antiviral compound developed by Pfizer, has been engineered to selectively inhibit the Mpro of SARS-CoV-2 by directly binding to its catalytic cysteine residue (Cys145). In a bid to scrutinize the expansive inhibitory spectrum of PF-07321332 against a gamut of human pathogenic coronaviruses, we undertook an exhaustive investigation leveraging molecular dynamics (MD) simulations in conjunction with binding free energy (BFE) calculations. Molecular dockings of PF-07321332 with the Mpros of seven human coronaviruses yielded their optimal binding modes (complexes), subsequently subjected to rigorous MD simulations and BFE assessments. The results of MD simulations indicated that PF-07321332 can remain stable in the substrate-binding cavity of all the seven human coronaviruses Mpros. A detailed comparison of BFE components revealed that intermolecular van der Waals (vdW) interactions play a significantly more crucial role in maintaining association and determining the high binding affinity than intermolecular electrostatic interactions. Analyses of residue BFE decomposition reveals Cys145 as a pivotalt amino acid, positively influencing the stable binding between Mpros and inhibitor. These finding imply that PF-07321332 has the potential to be an effective anti-coronavirus inhibitor and also provide insights into inhibitor optimization and drug design strategies against human coronavirus.