The human prion protein gene (PRNP) consists of two common alleles that encode either methionine or valine residues at codon 129. Polymorphism at codon 129 of the prion protein (PRNP) gene is closely associated with genetic variations and susceptibility to specific variants of prion diseases. The presence of these different alleles, known as the PRNP codon 129 polymorphism, plays a significant role in disease susceptibility and progression. For instance, the prion fragment 127-132 (PrP127-132) has been implicated in the development of variant Creutzfeldt-Jakob disease (vCJD), due to the presence of methionine or valine at codon 129. This study aims to unravel the early structural changes brought by the presence of polymorphism at codon 129. Using molecular dynamics (MD) simulations, we present evidence highlighting a spectrum of structural transitions, uncovering the nuanced conformational heterogeneity governing the polymorphic behavior of the PrP127-132 chain. The Markov state model (MSM) analysis was able to predict several metastable states of these chains and established a kinetic network that describes transitions between these states. Additionally, the MSM analysis showed extra stability of the PrP-M129 polymorph due to less random-coiled motions, the formation of a salt bridge, and an increase in the number of native contacts. The pathogenicity of PrP-V129 can be attributed to enhanced random motion and the absence of a salt bridge.

A large population in the world lives in tropical and subtropical regions, showing a high risk of Zika viral infection which leads to a situation of global health emergency and demands extensive research to create effective antiviral medicines. Herein, we introduce the design of a new derivatized trans-stilbene molecule to investigate the inhibition of Zika virus entry into the host cell by molecular docking approach. The synthesized compound has been characterized by different analytical techniques such as FTIR, H NMR,C NMR and UV-visible spectroscopy as well as Mass spectrometry (MS). Moreover, the complete structure elucidation was achieved via X-ray crystallography and DFT analysis. The article describes the life cycle and genome of the Zika virus along with its mechanism of entry inhibition by illustrating the structure and function of the ZIKV envelop (E) protein. The docking studies disclosed that the newly synthesized stilbene compound confers an excellent inhibitory response towards the entry of Zika virus in host cells as supported by calculated docking score and its binding conformation with Zika virus E-protein. Further, the normal mode analysis (NMA) simulation technique is used to predict the conformational states of the target E-protein, which explains the potency of the compound to bind with the Zika virus E-protein. We hope that the present study will help and encourage researchers in the field of medicinal chemistry to develop potential drugs against the Zika virus.

The DFT was employed to assess the ion-storage capability of an irida-graphene monolayer (IGM) in Mg-ion batteries (MIBs). The IGM had a mechanically stable structure. The IGM also exhibited great conductance based on the DOS calculations. The energy density of the IGM for MIBs was 3139.60 mWh g and its storage capacity was 1643.21 mAh g. Moreover, the Mg ions migrated easily across the IGM surface throughout cycle, as indicated by the increased rate of diffusion (1.58 x 10 cms) and the small energy barrier (0.068 eV). In addition, the obtained OCV for MIBs was 0.18 V, which was in line with the requirements for commercial designing. The current theoretical study demonstrated the possibility of using the IGM as an electrode in future MIBs.

PqsE and RhlR, key regulators of the Pseudomonas aeruginosa quorum sensing (QS) system, form a hetero-tetrameric complex essential for controlling the expression of virulence factors such as pyocyanin. The interaction between the PqsE homodimer and the RhlR homodimer bound to C4-HSL, enables RhlR to bind low-affinity promoters, thereby influencing gene regulation. Recent studies suggest that RhlR transcriptional activity is modulated by temperature, exhibiting higher activity at environmental temperatures (25 °C) compared to mammalian body temperature (37 °C). However, the molecular mechanisms underlying this temperature-dependent regulation remain unclear. This study aims to explore how temperature influences the structural stability of the PqsE/RhlR/C4-HSL complex using molecular dynamics (MD) simulations at 25 °C and 37 °C. The results demonstrate that the overall stability of the complex decreases at 37 °C, with global RMSD analysis indicating greater fluctuations compared to 25 °C. Further RMSD analysis of PqsE and RhlR separately revealed that the destabilization is more pronounced in RhlR, particularly in its DNA-binding domain (DBD), where significant flexibility and destabilization were observed at 37 °C, as indicated by the higher RMSF values. Free energy landscape analysis confirmed increased conformational flexibility in the RhlR at higher temperatures, potentially impairing its DNA-binding ability. To further investigate this, metadynamics simulations were performed for PqsE/RhlR/C4-HSL bound to DNA, revealing a remarkable increase in the distance between RhlR and DNA at 37 °C, potentially leading to a faster separation. These findings indicate that temperature-induced destabilization of RhlR, especially in the DBD, may explain the reduced RhlR transcriptional activity observed at mammalian body temperature.

In human eye, structural proteins, known as crystallins, play a crucial role in maintaining the eye's refractive index. These crystallins constitute majority of the total soluble proteins found in the eye lens. Among them, α-crystallins (α-CR) is one of the major components. Under hyperglycaemic conditions, crystallins become susceptible to glycation that ultimately leads to advanced glycation endproducts (AGEs) formation. Glipizide is a well-known oral medication used in controlling levels of blood sugar, this drug stimulates the insulin release from pancreas. However, this drug has not been thoroughly investigated for its impact on α-CR glycation. In this study, we explored glipizide's protective role against glucose-induced α-CR glycation. Remarkably, glipizide effectively inhibited the formation of early glycation products, ultimately reducing AGEs formation. Additionally, glipizide provides protection against modifications of free lysine residues and lowered the carbonyl content. To gain deeper insights into mechanism of inhibition, we turn to binding studies and bioinformatics. Glipizide formed stable complex with α-CR with values of Gibbs energy ranging from -5.848 to -6.695 kcal/mol. Molecular docking revealed the binding energy as -6.5 kcal/mol and lysine residues emerged as a prominent among the key interacting residues. Notably, glipizide appears to mask lysine residues, thereby contributing to the inhibition of α-CR glycation. Furthermore, analysis of molecular simulation data reinforces the stability of this complex. Consequently, the stable α-CR-glipizide complex may prevent glucose from binding to α-CR. Overall, glipizide holds promise as a preventive measure against glycation of eye lens proteins, potentially benefiting in diabetic retinopathy.

MXenes quantum dots (QDs), including NbC, NbCO, and NbCF, are emerging materials with exceptional structural, electronic, and optical properties, making them highly suitable for biomedical applications. This study investigates the structural optimization, stability, electronic properties, and drug-loading potential of these QDs using fluorouracil (Flu) as a model drug. Structural analyses show that the functionalization of NbC with O and F atoms enhances stability, with binding energies (BEs) of 7.335, 8.154, and 6.704 eV for NbC, NbCO, and NbCF, respectively. The drug-loading study reveals that NbC exhibits the highest adsorption energy of -6.775 eV at the surface site (2.053 Å), while NbCO and NbCF demonstrate weaker interactions with adsorption energies of -2.163 eV and -0.933 eV, respectively. Non-covalent interaction (NCI) and natural bond orbital (NBO) analyses show significant changes in electron density distribution upon drug interaction, with the natural charge on the O7 atom in Flu shifting slightly upon interaction. Optical property investigations indicate a blue shift in the absorption spectra for NbCO (λ = 764.76 nm) and NbCF (λ = 1108.71 nm), compared to NbC (λ = 2612.00 nm), confirming the tunability of these materials for therapeutic applications. By addressing key challenges in drug delivery, such as stability, controlled release, and interaction strength, this study establishes NbCO and NbCF as promising nanocarriers, with the potential to improve drug efficacy and minimize side effects in targeted cancer therapies.

Diabetes mellitus, characterized by persistent hyperglycemia, remains a critical global health challenge. Inhibition of human pancreatic alpha-amylase, a key enzyme catalyzing carbohydrate digestion, is a promising approach to manage postprandial glucose levels. Cinnamomum zeylanicum, a medicinal plant known for its therapeutic potential, harbors bioactive compounds that can act as natural alpha-amylase inhibitors, though their mechanisms remain underexplored. In this study, molecular docking and 200 ns molecular dynamics (MD) simulations were employed to evaluate the inhibitory potential of 18 phytochemicals derived from Cinnamomum zeylanicum. Two lead compounds, 1HE (1,2,4a,5,6,8a-Hexahydro-1-isopropyl-4,7-dimethylnaphthalene) and C4B (cis-4-Benzyl-2,6-diphenyl-tetrahydropyran), exhibited superior binding affinities (-7.91 and -8.78 kcal/mol, respectively) compared to the FDA-approved inhibitors, acarbose (-8.2 kcal/mol) and miglitol (-5.6 kcal/mol). MD simulations confirmed the stability of the complexes, with RMSD values of 0.21 ± 0.02 nm for 1HE and 0.24 ± 0.03 nm for C4B, showing minimal structural deviations. Structural analyses, including radius of gyration (Rg) and solvent-accessible surface area (SASA), revealed stable and compact protein-ligand conformations. Notably, free energy landscape (FEL) analysis indicated that C4B induces multiple metastable states, suggesting a dynamic inhibitory mechanism potentially involving allosteric regulation. These results highlight 1HE and C4B as promising natural inhibitors with favorable stability, binding characteristics, and inhibitory mechanisms. Further in vitro and in vivo studies are warranted to validate their therapeutic potential as safe and effective alternatives for diabetes management.

Human 5-lipoxygenase (LOX) is a non-heme, Fe-containing LOX which catalyses the conversion of arachidonic acid (AA) to leukotriene A (LTA). LTA is subsequently converted to cysteinyl-LTs and LTB that cause bronchoconstriction and act as chemotactic and chemokinetic agent on human leukocytes, respectively. Leukotrienes play significant roles in inflammation in asthma, cardiovascular diseases, allergic rhinitis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and many more. Thus, in order to suppress LT formation for the management of such diseases, the intrinsic details of the structure of 5-LOX are crucial for the design/development of 5-LOX inhibitors. Here, we deciphered the role of various amino acids at the allosteric site of 5-LOX through molecular dynamics simulations. 3-O-Acetyl-11-keto-beta-boswellic acid (AKBA), a well-recognized allosteric inhibitor of 5-LOX, was used as reference compound. The consequences of amino acid mutations (R101, E108, H130, E134) on AKBA binding have been studied in silico. The changes were characterized at the interaction level. Our observations provide structural insights into crucial residues which are important for stabilizing the ligand at the allosteric site. Principal component analysis (PCA) was applied to the molecular dynamics simulation data to identify the structural fluctuations in the 5-LOX structure. The derived mechanistic details of allosteric 5-LOX inhibition may facilitate the development of novel therapeutics targeting 5-LOX.

The novel coronavirus disease (COVID-19) pandemic has resulted in 777 million confirmed cases and over 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Post Acute Sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. In this study, we have investigated all bisphosphonates (BPs) on the ChEMBL database which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies in Japan with minodronate could be valuable.

This study investigates the interaction of a synthetic bio-relevant molecule with C and BN nanorings, exploring their potential applications in sensing and drug delivery. Employing Density Functional Theory (DFT) at the ωB97XD level with the 6-31G(d,p) basis set, we computed the adsorption and electronic properties of the resulting nanocomplexes. A total of ten distinct configurations were identified for the interactions, with adsorption energies ranging from -6.75 to -12.62 kcal/mol for the C@target molecule and -9.01 to -18.46 kcal/mol for the BN@target molecule. Notably, alterations in the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) upon interaction suggest an enhancement in electrical conductivity. The effect of aqueous media was also examined, revealing an increase of approximately 2.0 Debye in the dipole moments of the most stable nanocomplexes. Additional analyses, including reduced density gradient (RDG), UV-Vis spectroscopy, and Quantum Theory of Atoms in Molecules (QTAIM), were conducted in both gas and aqueous phases. Our findings indicate that C and BN nanorings exhibit significant promise as candidates for drug delivery and sensing applications, particularly due to their enhanced electronic properties upon interaction with the bio-relevant molecule.

Monomer insertion, leading to the formation of an activated monomer complex, is a critical step in cationic ring-opening polymerization (CROP) of cyclic monomers, such as ε-caprolactone (CL). In this study, Density Functional Theory (DFT) calculations were employed to investigate the structural and electronic properties of four activated complexes at two Zr:B ratios (1:2 and 1:1), where Zr is the cationic zirconocene catalyst, Cp₂ZrMe⁺, and B is the borate cocatalyst, [MeB(CF)] or [B(CF)]. Steric hindrance at the reactive site was analyzed using topographic steric maps, while inter- and intramolecular interactions of the complex systems were examined through the Quantum Theory of Atoms in Molecules (QTAIM) and non-covalent interaction (NCI) analyses. The 1:2 ratio exhibited significant steric hindrance above and below the monomer plane, restricting access to the Cp₂ZrMe⁺ catalytic site and potentially limiting monomer insertion. In contrast, the 1:1 ratio displayed reduced steric congestion and stronger localized attractive forces at the catalytic site, facilitating better interactions with monomers and solvents. Conceptual DFT descriptors revealed that 1:1 systems had smaller HOMO-LUMO energy gaps, lower hardness, and higher electrophilicity, with 1:1@[B(C₆F₅)₄]⁻ identified as the most reactive complex. QTAIM identified key hydrogen bonding interactions, and the Zr-O bonds, distinguishing stability and reactivity across Zr:B ratios. These findings provide valuable insights into the steric and electronic effects on monomer-activated species, enabling the optimization of Zr:B ratios and cocatalyst conditions for improved polymerization efficiency.

Topological indices are numerical invariants that provide key insights into the structural properties of molecular graphs and are crucial in predicting physio-chemical and biological activities. This paper applies established computational methodologies for analyzing benzenoid networks and their application to polycyclic aromatic hydrocarbons (PAHs) through degree-based topological indices computed via M-polynomial and NM-polynomial approaches. By examining tessellations, including linear chain, hexagonal, rhomboidal, and triangular configurations alongside their line graphs, this work highlights the influence of molecular topology on biological activity. Notably, the line graph of hexagonal tessellations resembling Kagome structures exhibits the highest potential bioactivity, revealing additional connectivity patterns that offer a structured framework for early-stage drug discovery and potentially enhance the understanding of molecular interactions. These findings underscore the value of topological indices in identifying key structural features, reducing attrition rates in drug development, and improving screening technologies, contributing to efficient drug design.

Liquid crystals (LC) are widely used in various optical devices due to their birefringence, dielectric anisotropy, and responsive behavior to external fields. Enhancing the properties of existing LCs through doping with nanoparticles, including semiconductor quantum dots, offers a promising route for improving their performance. Among various nanoparticles, QDs stand out for their high charge mobility, sensitivity in the near-infrared spectral region, and cost-effectiveness. These attributes make them ideal candidates for integration with LCs. While liquid crystalline behavior arises from the collective ordering of molecules, the microscopic interactions between QDs and LC molecules remain an intriguing area of study to understand the underlying quantum-level mechanisms. In this study, we employ Density Functional Theory to investigate the interaction between GaAs quantum dot and a 5CB molecule. The 5CB molecule and Ga atoms were brought together gradually, and the corresponding changes in interaction energy and electron density distributions were calculated. The energy profiles reveal a clear distance-dependent interaction, with a minimum observed at 2.1 Å, indicating the formation of stable complexes. While the BVP86 functional slightly overestimated the interaction energy, the B3LYP functional produced more accurate results, confirming the feasibility of stable quantum dot - 5CB molecule complexes.

Elongation factor G (EF-G) is essential for protein synthesis in Mycobacterium tuberculosis (Mtb), positioning it as a promising target for anti-tubercular drug development. This study employs Structure-Based Drug Design (SBDD) to identify potential small molecule inhibitors that specifically target EF-G. Initially, binding hotspots on EF-G were pinpointed, and the binding modes of various compounds were analyzed. Through protein-protein interaction studies, several promising candidates were validated. Virtual screening and molecular docking techniques were utilized to evaluate the binding affinities and interactions of 20 candidate molecules with Mtb EF-G. Additionally, toxicity profiles of these compounds were assessed using predictive models, which indicated non-carcinogenic properties. To further refine the selection process, Support Vector Machine (SVM) and Random Forest models were applied to predict cell wall permeability. Notably, Asinex (8853) and Asinex (102619) emerged as top candidates, boasting high probability scores for effective permeability. Molecular docking and molecular dynamics (MD) simulations revealed that Asinex (8853), Asinex (102619), and Otava (79226) exhibited strong binding affinities and favorable conformations within the active site of Mtb EF-G. These findings suggest that these compounds have significant potential as inhibitors, warranting further investigation into their efficacy as novel anti-tubercular agents. Overall, this study emphasizes the value of Structure-Based Drug Design in identifying promising therapeutic candidates against tuberculosis by targeting essential bacterial factors like EF-G.

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. However, none of the structures of IL37 complexes have been experimentally characterized. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations. We modeled all protein-protein complexes of IL37 using a range of methods from homology modeling to AlphaFold2 multimer predictions. Models that successfully recapitulated experimental features underwent further analysis through molecular dynamics simulations. As positive controls, binary and ternary complexes of IL18 from PDB were included for comparison. Several key findings emerged from the comparative analysis of IL37 and IL18 complexes. IL37 complexes exhibited higher mobility than the IL18 complexes. Simulations of the IL37-IL18Rα complex revealed altered receptor conformations capable of accommodating a dimeric IL37, with the N-terminal loop of IL37 contributing significantly to complex mobility. Additionally, the glycosyl chain on N297 of IL18Rα, which contours one edge of the cytokine binding surface, acted as a steric block against the N-terminal loop of IL37. Further, investigations into interactions between IL37 and IL18BP suggested that a binding mode homologous to IL18 was unstable for IL37, indicating an alternative binding mechanism. Altogether, this study accesses to the structure and dynamics of IL37 complexes, revealing the structural underpinnings of the IL37's modulatory effect on the IL18 signaling pathway.

Technetium-99m plays a pivotal role in nuclear medicine, offering unique IMAGING capabilities due to its favorable physical and chemical properties. This study investigates the redox behavior and electronic structures of three representative Tc(V) oxo complexes, [TcO(HMPAO)], [TcO(Bicisate)], and [TcO(DMSA)], using computational techniques. Employing relativistic density functional theory with the Zero-Order Regular Approximation (ZORA), we analyze singlet-triplet energy gaps, Gibbs free energy changes, and redox potentials in neutral and acidic environments. The results highlight the significant influence of co-ligands on the electronic stabilization of complexes and their tendencies toward reduction and protonation. The findings also elucidate the role of Jahn-Teller distortions in shaping the redox properties of the studied complexes. Redox potential trends indicate enhanced reducibility in complexes with sulfur-based ligands, impacting their clinical utility. This study provides valuable insights into the design and optimization of technetium-based radiopharmaceuticals, emphasizing their stability and behavior under physiological conditions.

The Acinetobacter baumannii is a member of the "ESKAPE" bacteria responsible for many serious multidrug-resistant (MDR) illnesses. This bacteria swiftly adapts to environmental cues leading to the emergence of multidrug-resistant variants, particularly in hospital/medical settings. In this work, we have demonstrated the outer membrane protein 33-36 (Omp33-36) porin as a potential therapeutic target in A. baumannii and the regulatory potential of phytocompounds using an in-silico drug screening approach. Omp33-36 protein receptor was retrieved from the protein data bank and characterized as a receptor protein. The possible compounds (ligands) from three plants namely Andrographis paniculata, Cascabela thevetia, and Prosopis cineraria, were evaluated for their potential against bacterial infections based on prior investigations and selected for further analysis. Initially, seventy potential phytocompounds were identified and retrieved from IMPPAT database, followed by Physio-chemical characterizations and toxicity assessment using swissADME and ProTox server respectively. 15 compounds have shown significant drug-likeliness and were implemented for their interaction analysis with Omp33-36 using Autodock Vina. The docking study presented seven compounds with the best binding affinities, ranging from -7.2 kcal/mol to -7.9 kcal/mol and further, based on the potential of these compounds, 4 phytocompounds were introduced for molecular dynamic simulation for 200ns. During MD simulation, compounds Prosogerin, Quercitin and Tamarixetin have shown a substantial affinity for the Omp33-36 protein and binding energy ranging from -18 to -33 kcal/mol. Overall, the analysis depicted the two compounds, Quercitin and Tamarixetin, with the most consistent interactions and indicated promise as drug leads in regulating A. baumannii infection. However, in-vitro and in-vivo experimental validation are required to propose the selected phytomolecules as a therapeutic lead against A. baumannii.

Gas phase bond dissociation energies (BDE) O-H/N-H in hydroquinone (HQ), 4-aminophenol (AP), 1,4-phenylenediamine (PDA), 4-hydroxydiphenylamine (HDPA), N,N'-diphenyl-1,4-phenylenediamine (DPPDA) as well as in their phenoxyl/aminyl radicals have been determined using a combined technique of quantum chemical calculation. The technique included a series of DFT (PBE1PBE, TPSSTPSS, M06-2X), ab initio (DLPNO-CCSD(T)) methods with valence 3ξ-basis sets, composite methods of Gaussian family (G4) and Weizmann theory with ab initio Brueckner Doubles (W1BD), as well as reference reactions of different levels of structural similarity. W1BD method was used in combination with isodesmic reactions for BDE estimation (kJ∙mol) of compounds with the only aromatic fragment: BDE = 352.3 (HQ), 340.0 (AP), BDE = 371.2 (AP), 364.1 (PDA) - in molecules; and BDE = 230.4 (HQ), 228.8 (AP), BDE = 260.0 (AP), 257.1 (PDA) - in corresponding radicals. These values were further applied to estimate the BDEs in HDPA and DPPDA within the homodesmotic reference process and less resource-intensive ab initio methods: BDE = 341.4 (HDPA), BDE = 352.9 (HDPA), 351.3 (DPPDA) for molecules; BDE = 237.4 (HDPA), BDE = 247.4 (HDPA), 252.6 (DPPDA) for radicals. DFT methods give similar results but a slightly larger standard error of calculation. The found values of BDE(O-H/N-H) are compared with literature data; the effect of solvation on BDEs is discussed.

In this study, the need for efficient detection of volatile organic compounds (VOCs) in environmental monitoring, industrial safety, is addressed by investigating borophene-based B36 nanoclusters as gas sensors. Density functional theory (DFT) calculations were employed to examine the adsorption behavior of ethanol, isobutanol, and acetone on B surfaces, with a focus on vibrational modes, reactivity, and adsorption energies. It was found that acetone exhibits the strongest interaction with pristine B, indicating its potential for robust sensing applications. To further enhance sensor performance, the effects of doping B with nickel (Ni) and iron (Fe) atoms were explored. The electronic structure was significantly modified in Fe@B, showing strong chemisorption properties, while Ni@B showed less impact, serving as a counterexample. Additionally, conductivity, recovery time, and global reactivity parameters were analyzed, providing insights into the sensor's functionality. It is suggested that B nanoclusters, particularly Fe-doped systems, offer promising prospects for future gas sensor development and VOC detection.

S-adenosylmethionine (SAM)-dependent histamine N-methyltransferase (HNMT) is a crucial enzyme involved in histamine methylation, playing an important role in the epigenetic modification of biology. It entails the addition of methyl groups to histamine molecules, thereby regulating gene expression, cellular signal transduction, and other biological processes. Therefore, gaining a profound understanding of the detailed mechanism underlying HNMT-mediated methylation reactions is instrumental in elucidating the role of histamine methylation in biology. This study employed molecular dynamics (MD) simulations to assess the mechanism of cooperative catalytic reaction between the substrate-binding domain (S domain) and the cofactor-binding domain (C domain) of HNMT. The results indicated that the interplay between the cofactor (SAM) and the C domain was mostly unaltered by substrate Histamine (HSM) binding. Nevertheless, SAM binding could induce conformational changes in the S domain, thus creating a favorable environment for substrate recognition and catalysis. Additionally, key amino acid residues that significantly contributed to substrate binding were identified based on molecular mechanics-generalized Born surface area (MM/GBSA) calculations. These findings could serve as a theoretical basis for the design of potential inhibitors and modulators targeting HNMT.

The Hepatitis C virus (HCV) causes a variety of liver diseases, making it a global health issue that affects millions of people in the world. The NS3/4A protease has been considered a common target for anti-HCV treatments using direct-acting antiviral agents and their derivatives. Of the natural products that have been proposed for novel therapeutic product alternatives, the soft coral compounds are found to contain steroids with various bioactive properties for effective HCV treatments. They are screened to search for HCV inhibitors using computational approaches to screen for potential HCV inhibitors from the extracts of soft corals. Among 188 steroids considered, the five top compounds are selected for evaluation of binding affinities and stabilities using molecular docking and dynamics simulations, as well as with absorption, distribution, metabolism, excretion, and toxicity to assess the drug's performance.