Computational and umbrella sampling analysis of HER2 D769H and D769Y variants: mutation-specific structural alterations and drug interactions in breast cancer.

The animal and computational studies were conducted to elucidate the anti-inflammatory and analgesic potential of the Daidzein (isoflavone in nature). The molecular docking of the Daidzein was commenced against the inflammatory and analgesic targets i.e., COX-2 (Cyclooxygenase-2), ERK (Extracelluar receptor kinase), and TRPV1 (Transient receptor Potential Vanilloid 1) protein. The molecular docking was followed by the molecular dynamic (MD) simulation assess the dynamic stability of the complexes over time. Following MD simulation, the binding free energy calculations were conducted to determine the thermodynamic binding affinity. After the computational studies, the results were validated using the acetic acid-induced writhing and formalin-induced models. The molecular docking of the Daidzein showed multiple hydrophilic and hydrophobic interactions. The MD simulation analysis showed that the Daidzein_COX-2, Diadizein_ERK, and Daidzein_TRPV1 complex showed that complexes remains stable using RMSD (Root mean square deviation), RMSF (Root mean square fluctuations), RoG (Radius of Gyration), SASA (Solvent accessible surface area) and hydrogen bond analysis. The binding free energy calculations using MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) and MM-GBSA Molecular Mechanics Generalized-Born Surface Area) revealed favorable binding free energy and the total energy of the system remains negative. Furthermore, the Daidzein showed marked reduction in the writhing movement and increased the pain threshold. Similarly, the Daidzein also evidently reduced the Formalin-induced biphasic pain response in animals when the results were compared with the Disease control. In conclusion, the Daidzein portrayed promising anti-inflammatory and analgesic activities using computational and animal studies, however, additional studies will be required to employ it clinically.

In this study, the ketoprofen derivatives were evaluated against inflammation and nociception using comprehensive computational methods. These derivatives were synthesized by modifying the structure of ketoprofen, a well-known NSAID (nonsteroidal anti-inflammatory drug) used clinically for the management of pain and inflammation. The virtual screening was performed to predict the binding affinities of the ketoprofen-based acyl hydrazone derivatives with key inflammatory and pain-related targets including cyclooxygenase-2 (COX-2), Transient Receptor Potential menthol-8 (TRPV1), c-Jun N-terminal Kinase-3 (JNK3), Extracellular Receptor Kinase (ERK) and Purinergic Receptor Type Y1 (P2Y1) to obtain the top hits. The virtual screening studies revealed the top hits such as COMP2, COMP10, COMP16 and COMP17 against the target protein. Based on the virtual screening, Molecular Dynamic (MD) simulation was performed on the top hits for 50 ns by using parameters like Root Mean Square Fluctuations (RMSF), Root Mean Square Deviation (RMSD), Radius of Gyration (RoG), Solvent Accessible Surface Area (SASA) and hydrogen bonds. The three complexes showed significantly lowered RMSD value and hence, the complexes remained stable throughout the simulation. For binding free energy, Molecular, Mechanics-Poison Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) were performed after MD simulation for the analysis of stability in the context of energy. The MM-PBSA and MM-GBSA evaluation showed overall energy of the system remains negative and indicates favorable binding interaction and hence, stability of the complexes. Furthermore, the per-residue decomposition was carried out to evaluate each amino acid involved in the ligand-protein interaction, and highest contributing amino acid in terms of energy involved in the ligand-protein interactions. The binding free energy calculation was succeeded by Density Functional Theory (DFT) analysis to evaluate the Highest Occupied Molecular Orbital (HOMO), Lowest Unoccupied Molecular Orbital (LUMO) and the HOMO-LUMO gap. In conclusion, the four compounds showed significant activity against pain and inflammation based on the computational analysis; however, to employ it clinically further analysis will be required.

Objective: This study explored the potential of dietary polyphenols from whole green jackfruit flour as natural Sodium-Glucose Co-Transporter-2 (SGLT-2) inhibitors for managing hyperglycemia in diabetes mellitus. Methods: Advanced bio-computational techniques, including molecular docking, Molecular Dynamics (MD) simulations, and binding free energy calculations, were employed to identify and assess polyphenols from jackfruit flour. Caffeic and syringic acids were highlighted for their strong binding affinities to the SGLT-2 receptor. Additionally, a ligand-based pharmacophore model was developed using caffeic acid as a reference to screen for new lead compounds in commercial and natural product databases. Results: The study found that caffeic acid and syringic acid exhibited stronger binding affinities and more stable interaction profiles with the SGLT-2 receptor than the standard drug empagliflozin. MD simulations demonstrated that these compounds provided greater stability in the binding site, indicating their potential efficacy as SGLT-2 inhibitors. The pharmacophore screening further supported these findings, identifying both compounds as promising lead candidates. Among the 14 dietary polyphenols obtained from High-Performance Liquid Chromatography (HPLC), a molecular docking study suggested that caffeic acid (binding affinity:-9.0 kcal/mol) and syringic acid (binding affinity:-9.1 kcal/mol) exhibited stronger binding affinities and more stable interaction profiles with the SGLT-2 receptor compared to the standard drug empagliflozin (binding affinity:-10.4 kcal/mol). Further, molecular dynamics simulations demonstrated that these compounds provided greater stability in the binding site, indicating their potential efficacy as SGLT-2 inhibitors through Root mean Square Deviation (RMSD), Root mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and ligand hydrogen bonds. The pharmacophore screening further supported these findings, identifying both compounds as promising lead candidates. Conclusion: This study is the first to identify caffeic acid and syringic acid from whole green jackfruit flour as effective SGLT-2 inhibitors. These natural compounds show significant potential as novel agents for managing hyperglycemia and diabetes mellitus. The findings support further exploration of plant-derived therapies in diabetes treatment.

Obesity is a growing public health concern, particularly in Malaysia, where prevalence rates continue to rise. Despite the availability of pharmacological interventions, existing anti-obesity drugs are often limited by modest efficacy and undesirable side effects. Natural compounds have emerged as promising alternatives, offering multi-target therapeutic potential with improved safety profiles. Karanjin, a furanoflavonoid isolated from Pongamia pinnata, has demonstrated anti-inflammatory and antioxidant activities, but its role in obesity management remains largely unexplored. In this study, an integrated in silico method was employed to explore the anti-obesity potential of Karanjin. Pharmacokinetic profiling indicated favourable absorption, distribution, and toxicity profiles. Network pharmacology analysis identified 145 overlapping targets between Karanjin and obesity-related genes, with enriched significant pathways such as AGE-RAGE signalling, which is implicated in oxidative stress and metabolic dysregulation. Molecular docking against eight hub proteins revealed strong binding affinities, with Karanjin exhibiting superior binding energies compared to reference anti-obesity drugs. Notably, the PIK3CA-Karanjin complex demonstrated the most favourable interaction profile. Confirmed molecular dynamics simulations results in a stable structure of the PIK3CA-Karanjin complex in a span of 100 ns, supported by root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), and solvent accessible surface area (SASA) analyses. Binding free energy calculations using the molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method further validated the thermodynamic favourability of the interaction. Collectively, the findings provide a strong computational foundation supporting the potential of Karanjin as a multi-target candidate for obesity management, warranting further experimental validation.

Alzheimer's disease (AD) is a serious threat to the global health care system and is brought on by a series of factors that cause neuronal dysfunction and impairment in memory and cognitive decline. This study investigated the therapeutic potential of phytochemicals that belong to the ten regularly used spice plants, based on their binding affinity with AD-associated proteins. Comprehensive docking studies were performed using AutoDock Vina in PyRx followed by molecular dynamic (MD) simulations using AMBER 14. The docking study of the chosen molecules revealed the binding energies of their interactions with the target proteins, while MD simulations were carried out to verify the steadiness of bound complexes. Through the Lipinski filter and admetSAR analysis, the chosen compounds' pharmacokinetic characteristics and drug likeness were also examined. The pharmacophore mapping study was also done and analyzed for best selected molecules. Additionally, principal component analysis (PCA) was used to examine how the general motion of the protein changed. The results showed quercetin and myricetin to be potential inhibitors of AChE and alpha-amyrin and beta-chlorogenin to be potential inhibitors of BuChE, exhibiting best binding energies comparable to those of donepezil, used as a positive control. The multiple descriptors from the simulation study, root mean square deviation (RMSD), root mean square fluctuation (RMSF), hydrogen bond, radius of gyration (Rg), and solvent-accessible surface areas (SASA), confirm the stable nature of the protein-ligand complexes. Molecular mechanic Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations indicated the energetically favorable binding of the ligands to the protein. Finally, according to pharmacokinetic properties and drug likeness, characteristics showed that quercetin and myricetin for AChE and alpha-amyrin and beta-chlorogenin for BuChE were found to be the most effective agents for treating the AD.

Computational exploration of novel ketoprofen derivatives: Molecular dynamics simulations and MM-PBSA calculations for COX-2 inhibition as promising anti-inflammatory drugs

Insighting the inhibitory potential of novel modafinil drug derivatives against estrogen alpha (ERα) of breast cancer through a triple hybrid computational methodology

The βC1 protein encoded by begomoviruses plays a key role in counteracting plant defense mechanisms, making it a prime target for antiviral compounds. Here, we investigated the role of plant secondary metabolites for their antiviral potential. Initially, the tertiary structure of βC1 protein was predicted and docked to 2851 plant secondary metabolites along with positive controls ribavirin and ningnanmycin. Additionally, 43 analogues of the ligand with highest dock score were created and assessed against the βC1 protein to see if they offered better binding energy than the initial compound. To check the protein–ligand complex's stability, we performed a 100 ns molecular dynamics (MD) simulation, then measured the change in Gibbs free energy (ΔG) using the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) approach. Our study found that Anonaine, a bioactive compound, had a high binding score of − 6.0 kcal/mol, with its analogues a33 and a41 scoring − 6.8 kcal/mol and − 6.6 kcal/mol, respectively. Molecular dynamics simulations for these complexes showed stable interactions, with minimal changes in root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values. Additionally, the protein–ligand complexes showed consistent hydrogen bond formation, with negligible changes in the radius of gyration (Rg) and solvent-accessible surface area (SASA). The binding free energy (ΔG) calculations revealed estimated values of − 16.99 ± 2.16, − 18.29 ± 1.91, and − 27.26 ± 2.11 for the βC1-Anonaine, βC1-a33, and βC1-a44 protein–ligand complexes, respectively. In silico toxicity predictions suggest top ligands are less toxic, making them ideal for biopesticide development. Overall, these findings reveal the potential of plant secondary metabolites as promising agents in controlling begomovirus infections.Graphical

Triosephosphate isomerase is an enzyme which catalyzes the inter-conversion between glyceraldehyde-3-phosphate and dihydroxyacetone phosphate in the fifth step of the glycolytic pathway. In this study, molecular dynamics simulation technique was employed to investigate the dynamics of the two monomer chains of triosephosphate isomerase of trypanosoma brucei brucei (TbTIM) using GROMACS 2016.04 software. The MD simulation of the x-ray structure of TbTIM was performed using the GROMOS 9643a1 force field and simple point charge water model under isothermal-isobaric condition with periodic boundary conditions imposed on x, y, z directions. The Root Mean Square Deviation (RMSD) Root Mean Square fluctuation (RMSF), Radius of Gyration (ROG), Solvent accessible surface area (SASA) and hydrogen bonds were computed. The RMSD values indicate that chain-B shows transition between two conformational states with higher RMSD value of 0.45 nm when compared to chain-A with RMSD of 0.27 nm. The RMSF values indicates that residues of loop 6 (residues 166 to 177) have the highest fluctuations in both chains compared to other residues with chain-A having higher fluctuations peak. The ROG values of chain-A varies from 1.675 nm to 1.761 nm while that of chain-B varies from 2.480 nm to 2.590 nm implying that chain-A is more compact during the simulation than chain-B. The SASA values indicates that chain-B has more contact with solvent than chain-A. 160 hydrogen bonds were found which indicates the stability of the protein during the simulation. From the RMSD, ROG, SASA values, it is evident that chain-B of triosephosphate isomerase of trypanosoma bruceibrucei displayed greater structural dynamics than chain-A during the MD simulation.

Aims: To investigate the pharmacological implications of the ligand cis-4-Benzyl-2,6- diphenyltetrahydropyran, focusing on its pathways, potential disease associations, and therapeutic applications in Type 2 Diabetes Mellitus (T2DM). Background: Cis-4-Benzyl-2,6-diphenyltetrahydropyran has been previously identified for its heightened binding affinity to T2DM targets. Understanding its diverse pathways and interactions with neurotransmitter signaling, neuronal receptors, and enzymes/metabolism can provide insights into its potential roles in disease modulation and therapeutic applications. Objectives: The primary objective of this study was to investigate the pharmacological effects of cis-4- Benzyl-2,6-diphenyltetrahydropyran in the context of Type 2 Diabetes Mellitus (T2DM). The study sought to understand its influence on neurotransmitter signaling, focusing on its modulation of G Protein-Coupled Receptors (GPCRs) and their role in diabetes pathogenesis. Utilizing KEGG pathway and gene ontology analyses, the study aimed to explore the ligand's involvement in neuroactive ligand-receptor interactions and the calcium signaling pathway, examining its broader impact on biological functions like inflammation, immune response, reproductive processes, and cellular metabolism associated with diabetes. Method: The study employed KEGG pathway and gene ontology analyses to profile cis-4-Benzyl-2,6- diphenyltetrahydropyran. The ligand's influence on neurotransmitter signaling, neuronal receptors, enzymes, and metabolic pathways was examined. Enrichment analysis was conducted to identify associated genes and pathways, focusing on the ligand's role in Neuroactive ligand-receptor interaction and the Calcium signaling pathway. Molecular docking and molecular dynamic simulations were performed to assess the ligand's interaction with the OPRK1 receptor, a G protein-coupled receptor implicated in metabolic regulation. Binding stability was analyzed using Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), and Solvent Accessible Surface Area (SASA). MMPBSA binding free energy analysis was conducted to validate the stability and strength of the ligand-receptor interaction. Result: The study revealed that cis-4-Benzyl-2,6-diphenyltetrahydropyran significantly impacts neurotransmitter signaling and cellular homeostasis by modulating GPCR pathways, including neuroactive ligand-receptor interaction and calcium signaling pathways. These pathways play critical roles in inflammation, immune response, reproductive processes, and cellular metabolism. Molecular docking and dynamic simulations demonstrated a strong and stable binding between the ligand and the OPRK1 receptor, a key GPCR implicated in metabolic regulation. The binding was supported by favorable binding free energy values (-255.58 kJ/mol) and consistent structural stability metrics, including minimal deviations in RMSD (0.2–0.4 nm) and stable radius of gyration (2.35–2.45 nm). Solvent Accessible Surface Area (SASA) analysis confirmed a compact ligand-receptor interaction, while hydrogen bonding reinforced binding specificity. These findings highlight the ligand's relevance in diabetes pathogenesis, particularly in regulating pathways involved in insulin sensitivity and glucose metabolism. Conclusion: This study advances our understanding of the cellular effects of cis-4-Benzyl-2,6- diphenyltetrahydropyran, highlighting its multifaceted potential in diabetes research. The strong interaction with OPRK1 suggests that the ligand could influence key pathways related to insulin sensitivity and metabolic regulation. However, the findings are derived from computational methodologies, and experimental validation through in vitro and in vivo studies is essential to confirm the ligand's biological activity and therapeutic relevance. The findings establish a foundation for targeted investigations and drug development, positioning this ligand as a promising candidate for therapeutic applications in diabetes mellitus.

Presbycusis is a clinical condition related to hearing impairment caused by chronic noise exposure, senescence, or genes that exacerbate the loss of the inner ear. Polycomb Chromobox (CBX) proteins regulate gene expression by targeting the Polycomb repressor complex 1 (PRC1) to histone H3K27me3 sites via their chromodomains, playing a key role in developing presbycusis. This study aims to search for new agents to decrease the progression of the hearing damage pathway CBX4. Initially, a review that identified 17 molecules with reported activity in auditory conditions was done. Molecular dynamics (MD) simulation was performed for the native protein and principal systems employing AMBER20 software. Root mean square deviation (RMSD), RMSF (root mean square fluctuation), solvent accessible surface area (SASA), radius of gyration (RoG) analyses, free energy molecular mechanics generalized born surface area (MMGBSA), and principal components analysis (PCA) calculations were obtained. The main results are that oridonin and curcumin have shown binding energy for the CBX4 protein, with higher affinity than UNC3688. In MDs, the CBX4-oridinin complex showed a more stable profile regarding RMSD and SASA, while the CBX4-curcumin compound evidenced better conformational and energetic stability. In conclusion, oridonin and curcumin could be potential inhibitors for CBX4.

Exploring <i>Artocarpus heterophyllus</i> phytochemicals as novel mineralocorticoid receptor inhibitors: A computational approach to hypertension therapy

Objective:This research aims to study the target specificity of selective bioactive compounds in complexing with the human angiotensin-converting enzyme (hACE2) receptor to impede the severe acute respiratory syndrome coronavirus 2 influx mechanism resulting in cardiac injury and depending on the receptor’s active site properties and quantum tunneling.Materials and Methods:A library of 120 phytochemical ligands was prepared, from which 5 were selected considering their absorption, distribution, metabolism, and excretion (ADMET) and quantitative structure–activity relationship (QSAR) profiles. The protein active sites and belonging quantum tunnels were defined to conduct supramolecular docking of the aforementioned ligands. The hydrogen bond formation and hydrophobic interactions between the ligand–receptor complexes were studied following the molecular docking steps. A comprehensive molecular dynamic simulation (MDS) was conducted for each of the ligand–receptor complexes to figure out the values – root mean square deviation (RMSD) (Å), root mean square fluctuation (RMSF) (Å), H-bonds, Cα, solvent accessible surface area (SASA) (Å2), molecular surface area (MolSA) (Å2), Rg (nm), and polar surface area (PSA) (Å). Finally, computational programming and algorithms were used to interpret the dynamic simulation outputs into their graphical quantitative forms.Results:ADMET and QSAR profiles revealed that the most active candidates from the library to be used were apigenin, isovitexin, piperolactam A, and quercetin as test ligands, whereas serpentine as the control. Based on the binding affinities of supramolecular docking and the parameters of molecular dynamic simulation, the strength of the test ligands can be classified as isovitexin > quercetin > piperolactam A > apigenin when complexed with the hACE2 receptor. Surprisingly, serpentine showed lower affinity (−8.6 kcal/mol) than that of isovitexin (−9.9 kcal/mol) and quercetin (−8.9 kcal/mol). The MDS analysis revealed all ligands except isovitexin having a value lower than 2.5 Ǻ. All the test ligands exhibited acceptable fluctuation ranges of RMSD (Å), RMSF (Å), H-bonds, Cα, SASA (Å2), MolSA (Å2), Rg (nm), and PSA (Å) values.Conclusion:Considering each of the parameters of molecular optimization, docking, and dynamic simulation interventions, all of the test ligands can be suggested as potential targeted drugs in blocking the hACE2 receptor.

Systematic identification and repurposing of FDA-approved drugs as antibacterial agents against Streptococcus pyogenes: In silico and in vitro studies

Emerging pollutants such as 4-nonylphenol (4-NP) act as endocrine disruptors and have been associated with reproductive toxicity in humans and wildlife, as well as with physiological disturbances in aquatic, terrestrial, and plant organisms. Laccases are oxidoreductases with notable biotechnological relevance and the ability to oxidize phenolic pollutants, making them attractive candidates for biodegradation strategies. This study investigated the interactions between laccases from Trametes villosa and Trametes lactinea and 4-NP and its degradation intermediates via molecular docking and molecular dynamics simulations (MDS). Ligands were geometrically optimized using the PM7 semiempirical method, and their global reactivity descriptors were computed to explore correlations between electronic properties and laccase binding affinity. Docking revealed favorable binding energies (ΔGbind ≈ -6kcal·mol-1) and recurrent interactions with key amino acid residues, including Ala, Glu, Leu, Phe, Pro, Ser, Val, and His, mainly through hydrogen bonding and hydrophobic contacts. The MDS confirmed the stability of the enzyme-ligand complexes, as indicated by low root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values, along with consistent radius of gyration and solvent-accessible surface areas throughout the trajectories. Binding free energy calculations using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method indicated stronger binding affinity under solvation, with ΔGbind values of -26.45 and -17.73kcal·mol-1 for T. villosa and T. lactinea, respectively, highlighting hydrophobic and van der Waals contributions as the primary stabilizing forces. Overall, these results provide computational evidence that laccases from T. villosa and T. lactinea have potential for application in the oxidative biodegradation of 4-NP. These findings advance the molecular understanding of fungal laccase‒pollutant interactions and support future in vitro validation and protein engineering strategies aimed at enhancing biodegradation efficiency.