Stable Hydrogen Bonds Research Articles

Hydroxyl and amino co-modified imidazole based ionic liquid functionalized TS-1 molecular sieve for efficient CO2 capture

Herein, an integrative solid adsorbent of [AHOPMIm]Cl with hydroxyl and amino groups functional sites modified TS-1 molecular sieve is designed and fabricated for efficient CO2 adsorption. The optimal [AHOPMIm]Cl/TS-1 exhibits 73% enhancement in CO2 adsorption capacity compared with the TS-1 molecular sieve, even outperforming other state of the art adsorbent systems. The greatly improved CO2 adsorption capacity is mainly attributed to the strong adsorption of amino groups on the ionic liquids surface, which can form low-temperature stable amino ester species. Moreover, it is preserved that the hydroxyl groups on the surface of ionic liquids can form stable hydrogen bonds with oxygen atoms in CO2, and coordinate with amino groups to capture CO2 from different directions based on in situ DRIFTS and DFT. The porous TS-1 molecular sieve provides a structural basis for the uniform dispersion, effective support, and enhanced CO2 adsorption capacity of ionic liquids. A new design concept for constructing ionic liquid-based composite adsorbent with dual functional sites using TS-1 molecular sieve as a carrier is provided, and the avenues for efficient CO2 adsorption are paved.

Novel bibenzyl compound 8Ae induces apoptosis and inhibits glycolysis by detaching hexokinase 2 from mitochondria in A549 cells

In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.

Exploring the competitive inhibition of α-glucosidase by citrus pectin enzymatic hydrolysate and its mechanism: An integrated experimental and simulation approach

The endo-polygalacturonase D (PgaD) from Aspergillus niger JL15 was recombinantly expressed in Escherichia coli BL21, exhibiting an optimal activity at 55 °C and pH 4.0. Hydrolysis products of citrus pectin by recombinant PgaD included galacturonic acid (GalA), digalacturonic acid (GalA2), trigalacturonic acid (GalA3), and tetragalacturonic acid (GalA4). The hydrolysates exhibited significant antioxidant capacity and dose-dependent competitive inhibition of α-glucosidase. GalA2 and GalA3 acted as competitive inhibitors of α-glucosidase, with inhibition constant of 0.0589 mmol.L−1 and 0.6732 mmol.L−1, respectively. Molecular dynamics (MD) simulations revealed that both GalA2 and GalA3 penetrated the catalytic pocket of α-glucosidase and formed stable hydrogen bonds with key catalytic residues D352 and D215. The binding free energies of GalA2-α-glucosidase and GalA3-α-glucosidase complexes were − 10.3 ± 0.6 kcal·mol−1 and -10.8 ± 0.7 kcal·mol−1, respectively. These findings might offer new ideas for the development of α-glucosidase inhibitors sourced from citrus pectin, as well as enhance utilization of the renewable plant polysaccharide resources.

Virtual screening and network pharmacology-based synergistic coagulation mechanism identification of multiple components contained in compound Kushen Injection against hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a primary liver malignancy commonly encountered in the setting of chronic liver disease and cirrhosis. Compound Kushen Injection (CKI) has been widely used in HCC, however, the underlying mechanisms are scarce. ObjectiveTo explore the molecular mechanisms of CKI for HCC.To explore the molecular mechanisms of CKI for HCC. Materials and MethodsThe chemical ingredients of CKI were reviewed from published articles and the potential targets were got from Herbal Ingredients’ Targets Platform. Coagulation-related targets were from Kyoto Encyclopedia of Genes and Genomes and HCC-related targets were from Therapeutic Target Database, Gene Expression Omnibus, and The Cancer Genome Atlas. Then the CKI-Herb-Target and CKI-Herb-Target-HCC networks were built. The shared targets between CKI and HCC were used for functional enrichment through Metascape and the shared coagulation-related target was used for molecular docking and survival analysis. ResultsA total of 23 chemical ingredients and 41 potential targets shared between CKI and HCC were obtained. The results of functional enrichment indicated that several canonical pathways of CKI mostly participated in the treatment of HCC. Furthermore, a chemical ingredient of CKI formed a stable hydrogen bond link with the ASN-189 on PLG, with a best binding energy of −4.7 kcal/mol. Finally, PLG was confirmed as the shared coagulation-related target and interrelated with the prognosis of HCC. ConclusionCKI probably improves HCC prognosis through PLG. Our research undoubtedly deepened the understanding of the molecular mechanism of CKI anti-HCC.

Molecular insights and inhibitory dynamics of flavonoids in targeting Pim-1 kinase for cancer therapy.

Pim-1 kinase, a serine/threonine kinase, is often overexpressed in various cancers, contributing to disease progression and poor prognosis. In this study, we explored the potential of flavonoids as inhibitors of Pim-1 kinase using a combination of molecular docking and steered molecular dynamics (SMD) simulations. Our docking studies revealed two main binding orientations for the flavonoid molecules. The SMD simulations showed that the binding mode with higher pulling forces was linked to stronger inhibitory activity, with a strong positive correlation (R 2 ≈ 0.92) between pulling forces and IC50 values. Quercetin stood out as the most potent inhibitor, showing a pulling force of about 820pN and an IC_(5) 0 of less than 6µM. Further dynamic simulations indicated that quercetin's hydroxyl groups at the C3, C-5 and C-7 positions formed stable hydrogen bonds with key residues GLU-121, Leu-44 and Val-126, respectively enhancing its binding stability and effectiveness. Our results emphasized the critical role of the hydroxyl group at the C-3 position, which plays a pivotal function in effectively anchoring these molecules in the active site of Pim-1 kinase. Principal component analysis (PCA) of Pim-1 kinase's conformational changes revealed that potent inhibitors like quercetin, galangin, and kaempferol significantly restricted the enzyme's flexibility, suggesting potential inhibitory effect. These findings provide insights into the structural interactions between flavonoids and Pim-1 kinase, offering a foundation for future experimental investigations. However, further studies, including in vitro and in vivo validation, are necessary to assess the pharmacological relevance and specificity of flavonoids in cancer therapy.

Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins

Abstract The treatment of the various infections caused by Staphylococcus aureus has become challenging due to the evolving resistance against current therapeutics. In this study, the potentials of napthyridine and oxadiazole derivatives to serve as dual inhibitors of penicillin-binding protein 2a (PBP-2a) and FemA protein, which are crucial to resistance to methicillin-based drugs by S. aureus, were evaluated using molecular modeling techniques. Seventy-two compounds were subjected to molecular docking against the proteins, and the hit compounds were subjected to drug-likeness evaluation and in silico pharmacokinetics prediction. The compounds with good safety profiles were subjected to a 250-ns molecular dynamics (MD) simulation and other relevant analyses based on the MD trajectories. Five hit compounds were selected based on their high affinity for the targets as evidenced by their docking scores ranging from −8.6 to −10.1 kcal/mol for PBP-2a and −9.6 to −9.9 kcal/mol for FemA. These compounds also passed Lipinski’s rule of five evaluation with no violation and possessed high human intestinal absorption potential, showcasing their potential as orally administered therapeutic agents. However, three of the compounds were potential mutagens. MD simulation revealed that the final two compounds maintained stable interactions with the target proteins over 250 ns, with minimal deviations and fluctuations. Hydrogen bond stability and energy decomposition analysis further confirmed the strong binding affinity of the hit compounds compared to the control drug, methicillin. Conclusively, the compounds with the CID “135964525” and “44130718” are worthy of further experimental validation in the development of potential inhibitors of PBP-2a and FemA.

Bioinformatics analysis of the antigenic epitopes of L7/L12 protein in the B- and T-cells active against Brucella melitensis

Abstract The objective is to analyse the physicochemical properties, spatial structure and protein–protein interactions (PPIs) of L7/L12 protein using bioinformatics methods and predict their B- and T-cell epitopes to lay a theoretical foundation for developing a novel multiepitope vaccine (MEV). The National Center for Biotechnology Information (NCBI) database was searched for the amino acid sequences of L7/L12 from Brucella melitensis. In addition, the online softwares, ProtParam and ProtScale, were used to predict the physicochemical properties: NetPhos3.1 and CD-search to predict the phosphorylation sites and conserved domains; SOMPA and SWISS-MODEL to predict the secondary and tertiary structures; the STRING database to analyse the PPIs; and the IEDB, ABCpred, SVMTrip and SYFPEITHI databases to predict the B- and T-cell epitopes. L7/L12 was docked to Toll-like receptor 4 (TLR4), B-cell receptor (BCR), Major histocompatibility complex I-T cell receptor (MHC I-TCR) and MHC II-TCR complexes, respectively, and the binding ability of L7/L12 to the targeted receptors was tested. L7/L12, consisting of 124 amino acids, was determined to be a stable, intracellular, hydrophilic protein containing 6 phosphorylation sites and ribosomal protein-related conserved domains. α-helices accounted for 70.16 %, β-turns for 2.42 %, extended strands for 8.87 % and irregular coils for 18.55 % of the secondary structure. The PPIs indicated that L7/L12 was involved in the constitution of ribosomes and regulating the accuracy of the translation process. Three B-cells, two cytotoxic T lymphocytes and three helper T lymphocyte epitopes were finally screened by comparing multiple databases. L7/L12 binds to TLR4, BCR, MHC I-TCR and MHC II-TCR complexes and forms stable hydrogen bonds, respectively. L7/L12, which governs the translation curate of proteins, possesses several potentially advantageous epitopes, laying a theoretical foundation for designing MEVs.

Virtual Screening of Flavonoids against Plasmodium vivax Duffy Binding Protein Utilizing Molecular Docking and Molecular Dynamic Simulation.

Plasmodium vivax (P. vivax) is one of the highly prevalent human malaria parasites. Due to the presence of extravascular reservoirs, P. vivax is extremely challenging to manage and eradicate. Traditionally, flavonoids have been widely used to combat various diseases. Recently, biflavonoids were discovered to be effective against Plasmodium falciparum. In this study, in silico approaches were utilized to inhibit Duffy binding protein (DBP), responsible for Plasmodium invasion into red blood cells (RBC). The interaction of flavonoid molecules with the Duffy antigen receptor for chemokines (DARC) binding site of DBP was investigated using a molecular docking approach. Furthermore, molecular dynamic simulation studies were carried out to study the stability of top-docked complexes. The results showed the effectiveness of flavonoids, such as daidzein, genistein, kaempferol, and quercetin, in the DBP binding site. These flavonoids were found to bind in the active region of DBP. Furthermore, the stability of these four ligands was maintained throughout the 50 ns simulation, maintaining stable hydrogen bond formation with the active site residues of DBP. The present study suggests that flavonoids might be good candidates and novel agents against DBP-mediated RBC invasion of P. vivax and can be further analyzed in in vitro studies.

Structural Basis for Long Residence Time c-Src Antagonist: Insights from Molecular Dynamics Simulations.

c-Src is involved in multiple signaling pathways and serves as a critical target in various cancers. Growing evidence suggests that prolonging a drug's residence time (RT) can enhance its efficacy and selectivity. Thus, the development of c-Src antagonists with longer residence time could potentially improve therapeutic outcomes. In this study, we employed molecular dynamics simulations to explore the binding modes and dissociation processes of c-Src with antagonists characterized by either long or short RTs. Our results reveal that the long RT compound DAS-DFGO-I (DFGO) occupies an allosteric site, forming hydrogen bonds with residues E310 and D404 and engaging in hydrophobic interactions with residues such as L322 and V377. These interactions significantly contribute to the long RT of DFGO. However, the hydrogen bonds between the amide group of DFGO and residues E310 and D404 are unstable. Substituting the amide group with a sulfonamide yielded a new compound, DFOGS, which exhibited more stable hydrogen bonds with E310 and D404, thereby increasing its binding stability with c-Src. These results provide theoretical guidance for the rational design of long residence time c-Src inhibitors to improve selectivity and efficacy.

Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I

The charge states of titratable amino acid residues play a key role in the function of membrane-bound bioenergetic proteins. However, determination of these charge states both through experimental and computational approaches is extremely challenging. Cryo-EM density maps can provide insights on the charge states of titratable amino acid residues. By performing classical atomistic molecular dynamics simulations on the high resolution cryo-EM structures of respiratory complex I from Yarrowia lipolytica, we analyze the conformational and charge states of a key acidic residue in its ND1 subunit, aspartic acid D203, which is also a mitochondrial disease mutation locus. We suggest that in the native state of respiratory complex I, D203 is negatively charged and maintains a stable hydrogen bond to a conserved arginine residue. Alternatively, upon conformational change in the turnover state of the enzyme, its sidechain attains a charge-neutral status. We discuss the implications of this analysis on the molecular mechanism of respiratory complex I.

Molecular Dynamics Simulation of Lipid Nanoparticles Encapsulating mRNA.

mRNA vaccines have shown great potential in responding to emerging infectious diseases, with their efficacy and stability largely dependent on the delivery vehicles-lipid nanoparticles (LNPs). This study aims to explore the mechanisms by which LNPs encapsulate mRNA, as well as the effects of different N/P ratios and acid types in nucleic acid solutions on the structure and properties of LNPs, using the ethanol solvent injection method as the encapsulation technique. Six systems were designed, based on the composition and proportions of the existing mRNA vaccine mRNA-1273, and molecular dynamics (MD) simulations were employed to investigate the self-assembly process of LNPs. Ethanol was used as a solvent instead of pure water to better mimic experimental conditions. The results indicate that lipid components self-assemble into nanoparticles under neutral conditions, with the ionizable lipid SM-102 predominantly concentrating in the core of the particles. Upon mixing with nucleic acids in acidic conditions, LNPs undergo disassembly, during which protonated SM-102 encapsulates mRNA through electrostatic interactions, forming stable hydrogen bonds. Cluster structure analysis revealed that the four lipid components of LNPs are distributed sequentially from the outside inwards as DMG-PEG 2000, DSPC, cholesterol, and protonated SM-102. Moreover, LNPs constructed under low pH or low N/P ratios using citric acid exhibited larger volumes and more uniform distribution. These findings provide a scientific basis for further designing and optimizing LNP components to enhance the efficacy of mRNA vaccine encapsulation.

The Endocannabinoid Peptide RVD-Hemopressin Is a TRPV1 Channel Blocker.

Neurotransmission is critical for brain function, allowing neurons to communicate through neurotransmitters and neuropeptides. RVD-hemopressin (RVD-Hp), a novel peptide identified in noradrenergic neurons, modulates cannabinoid receptors CB1 and CB2. Unlike hemopressin (Hp), which induces anxiogenic behaviors via transient receptor potential vanilloid 1 (TRPV1) activation, RVD-Hp counteracts these effects, suggesting that it may block TRPV1. This study investigates RVD-Hp's role as a TRPV1 channel blocker using HEK293 cells expressing TRPV1-GFP. Calcium imaging and patch-clamp recordings demonstrated that RVD-Hp reduces TRPV1-mediated calcium influx and TRPV1 ion currents. Molecular docking and dynamics simulations indicated that RVD-Hp interacts with TRPV1's selectivity filter, forming stable hydrogen bonds and van der Waals contacts, thus preventing ion permeation. These findings highlight RVD-Hp's potential as a therapeutic agent for conditions involving TRPV1 activation, such as pain and anxiety.

Molecular Modeling Studies to Mimic the Binding Hypothesis of NEU3 Sialidase and EGFR in Nonsmall Cell Lung Carcinoma

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic ([Formula: see text]-H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients.

Exploring pathogenic SNPs and estrogen receptor alpha interactions in breast cancer: An in silico approach

The estrogen receptor 1 gene (ESR1) plays a crucial role in breast and mammary development in humans. Alterations such as gene amplification, genomic rearrangements, and missense mutations in the ESR1 gene are reported to increase the risk of breast cancer in humans. The purpose of this study is to analyze the missense mutations and molecular modeling of ESR1, focusing on the pathogenic SNP H516N, for a better understanding of disease risk and future benefits for therapeutic benefits. This SNP was selected based on its location in the binding pocket of ESR1 and its predicted impact on drug binding. The in silico analysis was performed by applying various computational approaches to identify highly pathogenic SNPs in the binding pocket of ESR1. The effect of the SNP was explored through docking and intra-molecular interaction studies. All SNPs in ESR1 were identified followed by the identification of the highly pathogenic variant located in the binding pocket of ESR1. The mutant model of the pathogenic SNP H516N was generated, and hydroxytamoxifen was docked with the wild-type and the mutant model. The mutant model lost the formation of stable hydrogen bonds with the active site residues and hydroxytamoxifen, which may result in reduced binding affinity and therefore, will predict the patient's response to estrogenic inhibitors.

Exploration of adsorption properties of organic corrosion inhibitors on layered double hydroxide nanosheet: A molecular dynamics simulation study

Understanding the adsorption of organic corrosion inhibitors with different functional groups on layered double hydroxide (LDH) nanosheet is crucial for the synthesis of these protective materials. In this study, the adsorption process of five deprotonated organic corrosion inhibitors—lactate (Lc), 2-hydroxybenzothiazole (2-OH-BTH), 2-mercaptoethanesulfonic acid (MS), N,N-dimethylethanolamine (DMEA), and eugenol (EG)—on LDH nanosheets was simulated. The adsorption rate, adsorption configuration, and adsorption stability between LDH nanosheet and organic corrosion inhibitors were investigated throughout the entire adsorption process. The study observed consistency in the adsorption rate and stability of these organic corrosion inhibitors in the following order: Lc > 2-OH-BTH > MS > DMEA > EG. Additionally, hydrogen bonds between the organic corrosion inhibitors and the LDH nanosheet is the primary mechanism driving adsorption. The number and stability of hydrogen bonds influenced both the adsorption rate and stability. It is noteworthy that 2-OH-BTH and DMEA have not previously been incorporated into LDH. There is potential for these two organic corrosion inhibitors to be modified for LDH, suggesting significant prospects for future research.

Identification and validation of autophagy-related genes influenced by paris polyphylla in tongue cancer using network pharmacology

BackgroundTongue squamous cell carcinoma (TSCC) represents the most prevalent form of head and neck squamous cell carcinomas, comprising approximately one-third of all oral cancers. Paris polyphylla(PP) exhibit promising anti-tumor properties, yet their underlying mechanisms remain elusive. This study offers novel insights into the molecular mechanisms underlying TSCC treatment with PP and establishes a theoretical basis for their clinical application.MethodsEmploying transcriptomics and network pharmacology methodologies, we identified autophagy-related key genes associated with the effects of PP. These genes were subjected to KEGG and GO enrichment analyses to determine their related functions. In vitro, CAL-27 cells were treated with 10, 30, and 60 μg/ml of PP for 24 h to assess tumor cell proliferation, apoptosis, and autophagy-related markers.Key findings.Molecular docking of MAPK3 and PSEN1 with PP revealed stable hydrogen bond interactions, indicating the therapeutic potential of these saponins in TSCC through the autophagy pathway. In vitro experiments demonstrated significant inhibition of proliferative activity in tongue squamous carcinoma CAL-27 cells and promotion of tumor cell apoptosis by PP. Western blot analysis confirmed alterations in the expression of autophagy markers P62, LC3B, and Beclin1 following treatment, suggesting activation of the autophagy pathway.ConclusionsOur results suggest that PP inhibits tumor cells through the autophagy pathway, in which MAPK3 and PSEN1 play a role as potential functional molecules.

Investigation of antitumor activity and albumin interaction of new sulfosalicylate-based complex by spectroscopic and computational approaches.

In the present study, the drug delivery by albumin protein and antiproliferetaive activity of new transition metal complex i.e., [Pd (phen)(SSA)] (where phen and SSA represent 1, 10 phenanthroline and sulfosalicylic acid, respectively) was investigated. DFT (density functional theory) calculations were conducted at B3LYP level with 6-311G(d,p)/aug-ccpVTZ-PP basis set for the purpose of geometry optimization, frontier molecular orbital (FMO) analysis, molecular electrostatic potential (MEP), and natural bond orbital (NBO) analysis. Experimental tests were conducted to preliminarily assess the lipophilicity and antitumor activity of the metal complex, resulting in promising findings. In-silico prediction was accomplished to assess its toxicity and bioavailability. To evaluate the binding of the newly formed complex with DNA (which results in halting the cell cycle) or serum albumin protein (drug transporter to the tissues), in-silico molecular modeling was employed. Experimental results (spectroscopic and non-spectroscopic) showed that the new compound interacts with each biomolecule via hydrogen bond and van der Waals interactions. Molecular docking demonstrated the binding of this complex to the DNA groove and site I of BSA occurs mainly through hydrogen bonds. Molecular dynamics simulation confirmed the interactions between [Pd (phen)(SSA)] with DNA or BSA through stable hydrogen bonds.

Computational Modeling Study of the Molecular Basis of dNTP Selectivity in Human Terminal Deoxynucleotidyltransferase.

Human terminal deoxynucleotidyl transferase (TdT) can catalyze template-independent DNA synthesis during the V(D)J recombination and DNA repair through nonhomologous end joining. The capacity for template-independent random addition of nucleotides to single-stranded DNA makes this polymerase useful in various molecular biological applications involving sequential stepwise synthesis of oligonucleotides using modified dNTP. Nonetheless, a serious limitation to the applications of this enzyme is strong selectivity of human TdT toward dNTPs in the order dGTP > dTTP ≈ dATP > dCTP. This study involved molecular dynamics to simulate a potential impact of amino acid substitutions on the enzyme's selectivity toward dNTPs. It was found that the formation of stable hydrogen bonds between a nitrogenous base and amino acid residues at positions 395 and 456 is crucial for the preferences for dNTPs. A set of single-substitution and double-substitution mutants at these positions was analyzed by molecular dynamics simulations. The data revealed two TdT mutants-containing either substitution D395N or substitutions D395N+E456N-that possess substantially equalized selectivity toward various dNTPs as compared to the wild-type enzyme. These results will enable rational design of TdT-like enzymes with equalized dNTP selectivity for biotechnological applications.

Exploring highly selective polymethoxy fenamate isosteres as novel anti-prostate cancer agents: Synthesis, biological activity, molecular docking, molecular dynamics, and ADME studies

In this study, we synthesized and characterized sixteen new polymethoxy-substituted hydrazone derivatives. These compounds were evaluated for their in vitro cytotoxic activity against human prostate cancer (PC3) and human umbilical vein endothelial (HUVEC) cell lines. Compounds 5, 6, 7, and 11 exhibited significant cytotoxic effects with high selectivity index. Molecular docking studies and MM-GBSA binding free energy calculations were performed against tubulin protein. Compound 7 emerged as a particularly promising candidate, displaying an IC50 value of 1.49 µM against PC3 cells and a selectivity index of 264. Compound 7 achieved impressive docking score -13.655 kcal/mol against tubulin and formed stable hydrogen bonds and π-π stacking interactions with key residues in this protein. MD simulations confirmed the stability of the 7-tubulin complex. ADME analysis indicated that compound 7 has favorable absorption, solubility, and permeability properties, with minimal rule violations. The SAR analysis highlighted the significance of specific functional groups in enhancing the compound's cytotoxic and binding properties. Overall, compound 7 is identified as a leading candidate due to its exceptional cytotoxicity, high selectivity index, strong binding affinities, and favorable pharmacokinetic profile, making it a top candidate for further investigation and development as a novel anticancer agent.

Effect of two activators on the gating of a K2P channel

TWIK-related potassium channel 1 (TREK1), a two-pore-domain mammalian potassium (K+) channel, regulates the resting potential across cell membranes, presenting a promising therapeutic target for neuropathy treatment. The gating of this channel converges in the conformation of the narrowest part of the pore: the selectivity filter (SF). Various hypotheses explain TREK1 gating modulation, including the dynamics of loops connecting the SF with transmembrane helices and the stability of hydrogen bond (HB) networks adjacent to the SF. Recently, two small molecules (Q6F and Q5F) were reported as activators that affect TREK1 by increasing its open probability in single-channel current measurements. Here, using molecular dynamics simulations, we investigate the effect of these ligands on the previously proposed modulation mechanisms of TREK1 gating compared to the apo channel. Our findings reveal that loop dynamics at the upper region of the SF exhibit only a weak correlation with permeation events/nonpermeation periods, whereas the HB network behind the SF appears more correlated. These nonpermeation periods arise from both distinct mechanisms: a C-type inactivation (resulting from dilation at the top of the SF), which has been described previously, and a carbonyl flipping in an SF binding site. We find that, besides the prevention of C-type inactivation in the channel, the ligands increase the probability of permeation by modulating the dynamics of the carbonyl flipping, influenced by a threonine residue at the bottom of the SF. These results offer insights for rational ligand design to optimize the gating modulation of TREK1 and related K+ channels.