RMSF Values Research Articles

Computational Insights into the Binding Potential of Natural Products against Pseudomonas aeruginosa Metallo-beta-lactamase VIM-1 to Combat Antibiotic Resistance.

Metallo-beta-lactamase VIM-1 significantly contributes to bacterial resistance against beta-lactam antibiotics, including carbapenems, in Pseudomonas aeruginosa, leading to high morbidity and mortality, especially in immunocompromised individuals. The bacterium's ability to evade many antibiotics poses a significant challenge, necessitating novel inhibitors to treat such infections. This study uses a computational approach to identify VIM-1 inhibitors from the Molport library of natural compounds. Three promising compounds-ZINC000044404209, ZINC000038140885, and ZINC000037538575-were selected through virtual screening based on high docking scores and Lipinski filter application. Re-docking confirmed their interactions with VIM-1's active site. Molecular Dynamics (MD) simulations revealed that ZINC000044404209 and ZINC000038140885 were structurally more stable than the control, shown by lower RMSD and RMSF values, stable hydrogen bonding, and compact radius of gyration values. Using the MMGBSA method, the calculations of free binding energy confirmed ZINC000038140885 had the most favorable binding energy of -108.13 kcal/mol, followed by ZINC000044404209 with -38.02 kcal/mol. These findings identify compounds with stronger binding and stability than existing controls, potentially serving as potent VIM-1 inhibitors. This in silico study provides valuable leads that warrant further experimental validation to develop new therapies against antibiotic-resistant P. aeruginosa.

Synthesis, antibacterial activity, in silico ADMET prediction, docking, and molecular dynamics studies of substituted phenyl and furan ring containing thiazole Schiff base derivatives.

This study synthesized eighteen phenyl and furan rings containing thiazole Schiff base derivatives 2(a-r) in five series, and spectral analyses confirmed their structures. The in vitro antibacterial activities of the synthesized analogs against two gram-positive and two gram-negative bacteria were evaluated by disk diffusion technique. Compounds (2d) and (2n) produced prominently high zone of inhibition with 48.3 ± 0.6 mm and 45.3 ± 0.6 mm against B. subtilis, respectively, compared to standard ceftriaxone (20.0 ± 1.0 mm). However, the antibacterial potency of the compounds with furan ring was more notable than that of phenyl ring-containing derivatives. Molecular docking and dynamic study were performed based on the wet lab outcomes of (2d) and (2n), where both derivatives remained in the binding site of the receptors during the whole simulation time with RMSD and RMSF values below 2 nm. In silico ADMET prediction studies of the synthesized compounds validated their oral bioavailability. A more detailed study of the quantitative structure-activity relationship is required to predict structural modification on bioactivity and MD simulation to understand their therapeutic potential and pharmacokinetics.

The insight into the intermolecular interactions between protamine and insulin lispro.

The insight into the intermolecular interactions between protamine and insulin lispro.

Unraveling the molecular mechanism of temperature-induced destabilization in the PqsE-RhlR complex of Pseudomonas aeruginosa at mammalian body temperature through classical molecular dynamics and metadynamics.

Unraveling the molecular mechanism of temperature-induced destabilization in the PqsE-RhlR complex of Pseudomonas aeruginosa at mammalian body temperature through classical molecular dynamics and metadynamics.

Phytochemical baicalin potentially inhibits Bcl-2 and VEGF: an in silico approach.

The rising prevalence of cancer cells exhibits uncontrolled growth and invasive and aggressive properties, leading to metastasis, which poses a significant challenge for global health. Central to cancer development are proteins such as NF-kB, p53, VEGF, and BAX/Bcl-2, which play important roles in angiogenesis, cell apoptosis regulation, and tumor growth. This in silico study evaluates the activity of six different natural as well as novel therapeutic strategies against cancer. Using a computational approach, i.e., virtual screening, molecular docking, and molecular dynamics (MD) simulations, the binding affinities and interactions of selected phytochemicals with cancer-specific proteins were analyzed. Key criteria for selection included binding affinity, molecular stability, and pharmacokinetic and toxicological properties. Post-selection, dynamics of ligand-protein interactions were further examined through MD simulations conducted using Desmond-Maestro 2020-4 on a Linux-based HP Z2 workstation, providing an insight into the conformational changes in the stability of the inhibitor-protein complexes. This was complemented by ADMET predictions to assess pharmacokinetics and toxicological profiles. Our findings reveal that out of six phytochemicals, baicalin exhibited the most promising results, with docking scores of -9.2 kcal/mol and -9.0 kcal/mol against Bcl-2 and VEGF receptors, respectively. The MD simulation (100 ns) confirmed the stability of baicalin-protein interactions, supported by hydrophobic interactions and intermolecular hydrogen bonds. The RMSD and RMSF values of baicalin exhibit an acceptable global minimum (3.5-6 Å) for p53, VEGF, and BAX/Bcl-2. This study highlights the potential of baicalin, a phytochemical known for anti-cancerous, anti-apoptotic, and anti-proliferative properties, as a promising candidate for cancer treatment. Further exploration and validation of its inhibitory mechanisms could open a promising avenue for therapeutic approaches in oncology.

Informatics Approach Towards Targeting HTR1B Pathways in Neuropharmacology for Migraine Treatment.

Migraine is a prevalent and debilitating neurological disorder, with current therapies often being ineffective and causing side effects. Recent studies in neuropharmacology present the serotonin 1B receptor (HTR1B) as a viable avenue of migraine treatment since it influences pain and vasoconstriction. This research broadly uses computational approaches to explain the 5-hydroxytryptamine receptor 1B (HTR1B) pathways in neuropharmacology for migraine treatment. Text mining results reveal 25 essential genes, and network pharmacology provides complex mechanisms among genes and proteins, revealing a sophisticated network consisting of 41 nodes and 361 edges. The protein structure and function were elucidated through high-resolution protein modeling and validation, yielding significant new information. The structure has a resolution of 2.05 Å and a C-score of 0.30. The virtual screening explored the best ligands, which had binding affinities ranging from -13.8 to -9.6 kcal/mol from a set of 25 molecules. Docking results indicated that FDA-approved ligands showed high binding affinities, ranging from -11.4 to -12.5 kcal/mol among other natural and synthetic libraries. The pharmacokinetic profiles of the potential drugs showed significant diversity in their solubility and lipophilicity qualities (F(2,6) = 15.13, p = 0.004), suggesting different levels of safety and efficacy. MD simulation clarified the dynamic interactions between the protein and ligand at 100ns. The RMSD values were stable within the 6.0-7.5 Å range, indicating a consistent structure. RMSF values revealed areas of flexibility in the protein. The toxicity risk assessment of Xaliproden indicated modest risks. This study provides a foundation for targeted HTR1B-based migraine therapies and highlights the value of informatics tools in accelerating drug discovery in neuropharmacology.

In Silico Screening of Rauwolfia Serpentina Phytochemicals as Orexin Receptor-2 Agonists for the Management of Narcolepsy

The neuropeptide orexin/hypocretin plays a crucial role in numerous physiological processes such as regulation of sleep/wakefulness, appetite and emotions. Dysregulation of orexin signaling has been implicated in hypersomnia, especially in narcolepsy, characterized by excessive daytime sleepiness (EDS), sudden loss of muscle tone while awake (cataplexy), sleep paralysis, and hallucinations. Lack of orexins contributes to the development of narcolepsy, thus small-molecule orexin receptor agonists are promising therapeutics for narcolepsy. In this study, we employed several bioinformatics tools to screen and identify effective phytochemicals of Rauvolfia serpentina that may act as Orexin 2 receptor (OX2R) agonists. In silico methods such as protein‒ligand interaction analysis, drug‒likeness evaluation, ADMET analysis, molecular docking, molecular dynamics simulation, and biological activity prediction, have been employed extensively. Among all screened phytochemicals from R. serpentina, both tetraphylline and yohimbine were identified as promising drug candidates due to their favorable ADMET profile, high docking scores, permeability of the blood‒brain barrier, and significant RMSD, RMSF, Rg, and SASA values. However, the study is solely based on in silico study, therefore in vitro and in vivo experimental studies are suggested to validate the potency and efficacy of these medications.

In silico Evaluation of Anacyclus pyrethrum Composition for Inhibition of Spike RBD-ACE-2 Interaction to Treat COVID-19

Background: The spike glycoprotein of SARS-CoV-2, via its S1-subunit, binds with host angiotensin-converting enzyme 2 (ACE-2) receptors, and its S2-subunit mediates the fusion of the virus to the host cell. The entry of SARS-CoV-2 inside the host cell can be prevented by inhibition of the receptor binding domain (RBD) of S1-subunit of the spike. Anacyclus pyrethrum, a native herb of Algeria, Spain and Morocco has antidepressant, analgesic, antimicrobial, anesthetic, antioxidant, anti-inflammatory, aphrodisiac, antidiabetic and immunostimulant effects. Still, its antiviral effect has not been established yet. Methodology: The present study deals with ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity), molecular docking and molecular dynamic simulation based investigation to evaluate the potential of Anacyclus pyrethrum constituents for effective spike RBD inhibition. Results: ADMET analysis revealed that 10 out of 12 significant constituents belongs to toxicity class 4 to 6 proving least toxicity of the plant extract with high LD50 values. Molecular docking analysis of 10 considered compounds revealed that morphinan-6-one, 4,5.alpha.-epoxy-3-hydroxy-17-methyl, a derivative of morphine (well-known analgesic and anti-inflammatory compound) gave the maximum negative binding energy of -6.9Kcal/mol in best-docked conformation with spike RBD having 2 hydrogen bonds. Molecular dynamic simulation disclosed effective RMSD, RMSF, and Rg values over the simulation trajectory with significant hydrogen bonding proving stable interaction of the compound with that of the spike RBD. Conclusion: Hence, all these outcomes revealed the outstanding potential of the Anacyclus pyrethrum extract to inhibit the spike RBD of SARS-CoV-2. Therefore, further in-vitro investigation can develop natural and effective treatments against COVID-19 disease.

In silico screening of Hippophae rhamnoides polyphenols targeting the RhoA protein as a potential liver cancer treatment.

In silico screening of Hippophae rhamnoides polyphenols targeting the RhoA protein as a potential liver cancer treatment.

Identification and Validation of B-Cell Epitopes on the VP1 Protein of Parvovirus B19 through Molecular Docking and Dynamics Simulation.

This study aimed to identify B-cell epitope candidates using multiple epitope identification software and in silico analysis of the modeled B19 V protein against specific antibodies using molecular docking and dynamics simulation. Materials and Methods : Full-length amino acid sequences of the VP1 protein of B19 V were retrieved from NCBI. A consensus sequence was generated using CLC sequence viewer. Linear B cell epitopes were identified using Bepipred 2.0, ABCpred, and LBTope. The linear epitope was synthesized and validated against B19 V-specific antibodies. A 3D model of the B19 V VP1 consensus protein was generated using the ITASSER server. Discontinuous B cell epitopes were identified using Discotope 2.0 and Ellipro. Molecular docking and molecular dynamics simulation was performed to investigate the interaction between the modeled B19 V protein and specific anti-B19 V antibody. Results : The identified epitope was 100% conserved and similarly identified through ABCpred and LBTope. The HADDOCK score and MDS analysis, such as hydrogen bond interactions and MMPBSA analysis, revealed that the VP1 and mAb H chains formed a significantly stable complex. The MDS demonstrated that the VP1-mAb H chain complexes had lower RMSF values around 130 to 200 residues, a region responsible for the catalytic network for enzyme activity; as a result, the flexibility of the antibody-bound VP1 decreased when compared to Apo-VP1. Conclusion: A viable epitope identified through this process was synthesized and validated using ELISA, which highlighted the role of the epitope identification process in diagnostics. This study also sheds light on the complex interplay between VP1 and the mAb H chain and highlights key binding specificity and stability determinants.

Identification of potent TMPRSS4 inhibitors through structural modeling and molecular dynamics simulations

TMPRSS4, a transmembrane serine protease type II, is associated with various pathological illnesses. It has been found to activate SARS-CoV-2, enhance viral infection of human small-intestinal enterocytes and is overexpressed in different types of cancers. Therefore, this study aims to disover potential TMPRSS4 inhibitors that have better binding affinity than the approved inhibitors: 2-hydroxydiarylamide and tyroserleutide. Since no 3D-structure is known for TMPRSS4, structural models for the TMPRSS4 serine protease domain were developed. The modeled structures were validated and subjected to molecular dynamics simulations. FDA-approved, clinical/preclinical drugs and natural products were docked to the pocket of TMPRSS4. Moreover, through a systematic analysis, MD simulations and MM-GBSA binding free energy calculations revealed that the best candidates Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 are highly stable drug candidates in complex with TMPRSS4, displaying low RMSD and RMSF values with strong binding stability. Among these compounds, Ergotamine showed the most favorable binding energy (-33.73 kcal/mol). Overall, our in silico results revealed that these compounds could act as potent TMPRSS4 inhibitors and need to be validated by future experimental studies.

Identification of novel cyclin-dependent kinase 4/6 inhibitors from marine natural products.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of cell cycle progression and represent important therapeutic targets in breast cancer. This study employs a comprehensive computational approach to identify novel CDK4/6 inhibitors from marine natural products. We utilized structure-based virtual screening of the CMNPD database and MNP library, followed by rigorous filtering based on drug-likeness criteria, PAINS filter, ADME properties, and toxicity profiles. From an initial hit of 9,497 compounds, 2,344 passed drug-likeness and PAINS filters. Further ADME filtering yielded 50 compounds, of which 25 exhibited non-toxic profiles. These 25 candidates underwent consensus molecular docking using seven distinct algorithms: AutoDockTools 4.2, idock, LeDock, Qvina 2, Smina, AutoDock Vina 1.2.0, PLANTS, and rDock. Based on these results, six top-scoring compounds were selected for comprehensive 500 nanosecond all-atom molecular dynamics simulations to evaluate their structural stability and interactions with CDK4/6. Our analysis revealed that compounds CMNPD11585 and CMNPD2744 demonstrated superior stability in their interactions with CDK4/6, exhibiting lower RMSD and RMSF values, more favorable binding free energies, and persistent hydrogen bonding patterns. These compounds also showed lower Solvent Accessible Surface Area values, indicating better compatibility with the CDK4/6 active site. Subsequent in-vitro studies using MTT assays on MCF-7 breast cancer cells confirmed the cytotoxic effects of these compounds, with CMNPD11585 showing the highest potency, followed by CMNPD2744.

Substituted piperazine conjugated to quinoline-thiosemicarbazide as potent α-glucosidase inhibitors to target hyperglycemia

Diabetes mellitus, particularly type 2 diabetes, is a growing global health challenge characterized by chronic hyperglycemia due to insulin resistance. One therapeutic approach to managing this condition is the inhibition of α-glucosidase, an enzyme involved in carbohydrate digestion, to reduce postprandial blood glucose levels. In this study, a series of thiosemicarbazide-linked quinoline-piperazine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity, to identify new agents for type 2 diabetes management. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the aryl ring significantly impacted the inhibitory potency. Among the synthesized derivatives, the 2,5-dimethoxy phenyl substitution (7j) exhibited the most potent activity with an IC50 value of 50.0 µM, demonstrating a 15-fold improvement compared to the standard drug acarbose. Kinetic studies identified compound 7j as a competitive inhibitor, with a Ki value of 32 µM. Molecular docking simulations demonstrated key interactions between compound 7j and the active site of α-glucosidase, while molecular dynamics simulations confirmed the stability of the enzyme-ligand complex, reflected in low RMSD and RMSF values.

Comparative analysis of biodesulfurization of dibenzothiophene (DBT) and 4,6-dimethyl dibenzothiophene (4,6-DMDBT) by 4S pathway using molecular simulations

In this paper, we have analyzed biodesulfurization of dibenzothiophene (DBT) and 4,6-dibenzothiophene (4,6-DMDBT) by 4S metabolic pathway using molecular simulations. Docking analysis revealed lower binding energies and inhibition constants (Ki ) for 4,6-DMDBT and its metabolic intermediates with DSZ enzymes than DBT and its intermediates. The complexes of substrate and its metabolites with DSZ enzymes had higher stability for 4,6-DMDBT than DBT owing to lower RMSF values than apoprotein. The docking analysis revealed affinity of the inhibitors HBPS and HBP (for DBT) and DMHBPS and DMHBP (for 4,6-DMDBT) toward DSZ enzyme due to negative binding energies. Molecular dynamics simulations showed stability of several enzyme–inhibitor complexes. The inhibitory effect of DMHBPS on DSZC enzyme (Ki = 1.53 µM) and DMHBP on DSZB enzyme (Ki = 3.87 µM) was most marked. The inhibitory effect of HBP on DSZC and DSZB enzymes was moderate due to Ki of 6.36 and 7.93 µM, respectively. The inhibition effect of DMHBP on the DSZA enzyme was insignificant due to high Ki of 53.6 µM. In summary, higher stability of enzyme–substrate complexes and strong inhibition by DMHBPS and DMHBP (due to very low Ki ) contribute to slower biodesulfurization of 4,6-DMDBT as compared to DBT.

Screening and evaluation of novel DPP-IV inhibitory peptides in goat milk based on molecular docking and molecular dynamics simulation.

Screening and evaluation of novel DPP-IV inhibitory peptides in goat milk based on molecular docking and molecular dynamics simulation.

In Silico and Network Pharmacology Approach for Mechanistic Exploration of Rhododendron arboreum Sm. Leaf in Nonalcoholic Fatty Liver Disease

Rhododendron arboreum Sm. (Burans) (family Ericaceae) has traditionally been used in Indian medicine to treat liver disorders. However, its mechanism against non-alcoholic fatty liver disease (NAFLD) remains elusive. This study utilized in silico methods – network pharmacology, ADMET prediction, molecular docking and molecular dynamics (MD) simulations for mechanistic exploration of Rhododendron arboreum leaves (RAL) in NAFLD. Bioactive compounds were sourced from open databases and assessed for drug-likeness and ADMET profiles. Network pharmacology identified key protein interactions using the STRING platform. GO analysis identified galactose metabolism, pentose and glucuronate interconversions and other processes in treating NAFLD. Molecular docking revealed that amyrin and pectolinarigenin had the highest binding affinities, with dock scores of –12.2 kcal/mol (AKR1C3-amyrin), –10.2 kcal/mol (PI3K-amyrin), –9.3 kcal/mol (AKR1C3-pectolinarigenin) and –9.6 kcal/mol (HSD17B1-pectolinarigenin). MD simulations, focusing on RMSD and RMSF analyses, confirmed the stability of these interactions. The RMSD graphs revealed stable binding pocket regions, highlighted in pink. Notably, the RMSF values for PHE (B:306) in the AKR1C3-amyrin complex and ARG (A:294) in the PI3K-amyrin interaction were 0.623 nm and 0.1586 nm, respectively, indicating stable ligand interactions. Our findings holistically clarify toxicity data, potential bioactives targets and molecular mechanisms of RAL against NAFLD, paving the way for future research.

Molecular dynamics-based computational investigations on the influence of tumor suppressor p53 binding protein against other proteins/peptides

The tumor-suppressing p-53 binding protein is a crucial protein that is involved in the prevention of cancer via its regulatory effect on a number of cellular processes. Recent evidence indicates that it interacts with a number of other proteins involved in cancer in ways that are not fully understood. An understanding of such interactions could provide insights into novel ways p53 further exerts its tumour prevention role via its interactions with diverse proteins. Thus, this study aimed to examine the interactions of the p53 protein with other proteins (peptides and histones) using molecular simulation dynamics. We opted for a total of seven proteins, namely 2LVM, 2MWO, 2MWP, 4CRI, 4X34, 5Z78, and 6MYO (control), and had their PBD files retrieved from the protein database. These proteins were then docked against the p-53 protein and the resulting interactions were examined using molecular docking simulations run at 500 ns. The result of the interactions revealed the utilisation of various amino acids in the process. The peptide that interacted with the highest number of amino acids was 5Z78 and these were Lys10, Gly21, Trp24, Pro105, His106, and Arg107, indicating a stronger interaction. The RMSD and RMSF values indicate that the complexes formed were stable, with 4CRI, 6MYO, and 2G3R giving the most stable values (less than 2.5 Å). Other parameters, including the SASA, Rg, and number of hydrogen bonds, all indicated the formation of fairly stable complexes. Our study indicates that overall, the interactions of 53BP1 with p53K370me2, p53K382me2, methylated K810 Rb, p53K381acK382me2, and tudor-interacting repair regulator protein indicated interactions that were not as strong as those with the histone protein. Thus, it could be that P53 may mediate its tumour suppressing effect via interactions with amino acids and histone.

Molecular docking and transcriptomic analysis reveal the mechanism of myosin-derived peptides activating bitter receptor of hT2R1

Molecular docking and transcriptomic analysis reveal the mechanism of myosin-derived peptides activating bitter receptor of hT2R1

COF-SO3H-Catalyzed Synthesis of Pyrazoline-Pyridine Hybrids with Dual Antioxidant and Anti-Inflammatory Activity Targeting PDE4B.

This study explores new anti-inflammatory agents by synthesizing pyrazoline-pyridine hybrids with N-butylsulfonated covalent organic framework (COF-SO3H) as a recyclable catalyst, achieving excellent yields in just one minute. The protocol was successfully scaled up to a multi-gram scale, highlighting its robustness and efficiency, and it operates without the need for column chromatography. Among the synthesized hybrids, compound 5d, a pyrazoline-pyridine hybrid bearing an indole moiety, emerged as a potent anti-inflammatory and antioxidant agent. It effectively inhibited PDE4B activation with an IC50 value of 99.38 nM, without adversely affecting HEK cells. Compound 5d demonstrated its dual activity by significantly reducing ROS production and restoring mitochondrial health in LPS-stimulated A549 and HEK cells, while also downregulating IL-1β and NF-ĸB/p65 expression in LPS-stimulated A549 cells. In silico studies confirmed compound 5d's strong binding to PDE4B, with stable RMSD and RMSF values, indicating its potential as a stable and effective PDE4B inhibitor. The compound exhibited favorable physicochemical properties, met drug-likeness criteria, and showed low toxicity as predicted in silico. These findings suggest that compound 5d has significant potential as a therapeutic agent for inflammatory diseases due to its dual anti-inflammatory and antioxidant activities.

Investigating the polyethylene degradation mechanism using docking and molecular dynamics simulations.

Polyethylene (PE), widely utilized in everyday life, is notorious for its protracted degradation period, extending over decades, presenting an environmental hazard. Recently, there has been growing interest in utilizing microorganisms to aid in PE decomposition. Molecular docking and molecular dynamics simulations are valuable tools for understanding specific mechanisms and conducting initial screenings to support experimental research in this context. In this study, various enzymes, including lignin peroxidase, laccase, manganese peroxidase, and cutinase, sourced from Phanerodontia chrysosporium, Melanocarpus albomyces, and Fusarium vanettenii, were investigated. The docking simulations revealed that lignin peroxidase exhibited the most substantial binding interaction with PE, displaying a binding energy of - 4.69162 kcal mol-1 and an RMSD value of 0.93428 Å. Following lignin peroxidase in binding strength were laccase, manganese peroxidase, and cutinase. Furthermore, molecular dynamics simulations provided insights into the binding mechanisms. These simulations demonstrated stability over a 200-ns period, as indicated by RMSD and RMSF values below 0.2 nm. Additionally, the study delved into the interaction mechanisms between microorganisms and plastic molecules, enriching our understanding of this process. While the findings of this study may be considered modest, they contribute to a broader perspective and have the potential to influence more profound and significant research in the field.