Molecular Dynamics Simulation Approach Research Articles

Phanto-IDP: compact model for precise intrinsically disordered protein backbone generation and enhanced sampling.

The biological function of proteins is determined not only by their static structures but also by the dynamic properties of their conformational ensembles. Numerous high-accuracy static structure prediction tools have been recently developed based on deep learning; however, there remains a lack of efficient and accurate methods for exploring protein dynamic conformations. Traditionally, studies concerning protein dynamics have relied on molecular dynamics (MD) simulations, which incur significant computational costs for all-atom precision and struggle to adequately sample conformational spaces with high energy barriers. To overcome these limitations, various enhanced sampling techniques have been developed to accelerate sampling in MD. Traditional enhanced sampling approaches like replica exchange molecular dynamics (REMD) and frontier expansion sampling (FEXS) often follow the MD simulation approach and still cost a lot of computational resources and time. Variational autoencoders (VAEs), as a classic deep generative model, are not restricted by potential energy landscapes and can explore conformational spaces more efficiently than traditional methods. However, VAEs often face challenges in generating reasonable conformations for complex proteins, especially intrinsically disordered proteins (IDPs), which limits their application as an enhanced sampling method. In this study, we presented a novel deep learning model (named Phanto-IDP) that utilizes a graph-based encoder to extract protein features and a transformer-based decoder combined with variational sampling to generate highly accurate protein backbones. Ten IDPs and four structured proteins were used to evaluate the sampling ability of Phanto-IDP. The results demonstrate that Phanto-IDP has high fidelity and diversity in the generated conformation ensembles, making it a suitable tool for enhancing the efficiency of MD simulation, generating broader protein conformational space and a continuous protein transition path.

Phytochemical profiling, in vitro analysis for anti-inflammatory, immunomodulatory activities, structural elucidation and in silico evaluation of potential selective COX-2 and TNF-α inhibitor from Hydrilla verticillata (L.f.) Royle

Hydrilla verticillata (L.f.) Royle is a perennial aquatic plant, which exhibits nutritional as well as therapeutic properties. The present study has been carried out to evaluate anti-inflammatory and immunomodulatory activities along with in silico evaluation of potential selective COX-2 and TNF-α inhibitors from methanolic extract of H. verticillata (L.f.) Royle. The potential therapeutic compounds have been identified by high-resolution GC-MS analysis. Its capacity to inhibit inflammatory responses using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells has been explored. The anti-inflammatory properties of the plant extract were investigated by inhibiting inducible nitric oxide (NO) synthase and reduced NO generation driven by LPS on stimulated RAW 264.7 macrophage cells. Further investigation for the underlying molecular mechanism of the anti-inflammatory activity of plant extract has been carried out by molecular docking and molecular dynamics simulation approaches with COX-2 and TNF-α inhibitors ability against the most potent phytocompound phytol from the plant extract. To evaluate whether the extract causes any toxicity, the cytotoxicity test has been carried out with the Human embryonic kidney cell line (Hek-293), Mouse fibroblast (L929), human mesenchyme stem cells (hMSCs) and human breast epithelial cell line (MCF-10a). Ultimately, our findings suggest that the plant extract have great potential to reduce inflammation without causing any toxicity to normal cell. Communicated by Ramaswamy H. Sarma

Methyl 4-pyridyl ketone thiosemicarbazone (4-PT) as an effective and safe inhibitor of mushroom tyrosinase and antibrowning agent

Enzymatic browning is of concern as it can affect food safety and quality. In this study, an effective and safe tyrosinase inhibitor and anti-browning agent, methyl 4-pyridyl ketone thiosemicarbazone (4-PT), was synthesised and characterised using Fourier-transform infrared (FTIR) spectroscopy, CHNS elemental analysis, and proton (1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopy. The vibrational frequencies of 4-PT were studied theoretically using vibrational energy distribution analysis (VEDA). Density functional theory (DFT) was applied to elucidate its chemical properties, including the Mulliken atomic charges, molecular electrostatic potential (MEP), quantum theory of atoms in molecules (QTAIM) and reduced density gradient non-covalent interactions (RDG-NCIs). Moreover, 4-PT was compared with kojic acid in terms of its effectiveness as a tyrosinase inhibitor and anti-browning agent. The toxicity and physicochemical properties of 4-PT were predicted via ADME evaluation, which proved that 4-PT is safer than kojic acid. Experimentally, 4-PT (IC50 = 5.82 μM, browning index (10 days) = 0.292 ± 0.002) was proven to be an effective tyrosinase inhibitor and anti-browning agent compared to kojic acid (IC50 = 128.17 μM, browning index (10 days) = 0.332 ± 0.002). Furthermore, kinetic analyses indicated that the type of tyrosinase inhibition is a mixed inhibition, with Km and Vmax values of 0.85 mM and 2.78 E-09 μM/s, respectively. Finally, the mechanism of 4-PT for tyrosinase inhibition was proven by 1D, second derivative and 2D IR spectroscopy, molecular docking and molecular dynamic simulation approaches.

Comparative Atomistic Insights on Apo and ATP-I1171N/S/T in Nonsmall-Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangements occur in about 5% of nonsmall cell lung cancer (NSCLC) patients. Despite being first recognized as EML4-ALK, fusions with several additional genes have been identified, all of which cause constitutive activation of the ALK kinase and subsequently lead to tumor development. ALK inhibitors first-line crizotinib, second-line ceritinib, and alectinib are effective against NSCLC patients with these rearrangements. Patients progressing on crizotinib had various mutations in the ALK kinase domain. ALK fusion proteins are activated by oligomerization through the fusion partner, which leads to the autophosphorylation of the kinase's domain and consequent downstream activation. The proposed computational study focuses on understanding the activation mechanism of ALK and ATP binding of wild-type (WT) and I1171N/S/T mutations. We analyzed the conformational change of ALK I1171N/S/T mutations and ATP binding using molecular docking and molecular dynamics simulation approaches. According to principal component analysis and free energy landscape, it is clear that I1171N/S/T mutations in Apo and ATP showed different energy minima/unstable structures compared to WT-Apo. The results revealed that I1171N/S/T mutations and ATP binding significantly supported a change toward an active-state conformation, whereas WT-Apo remained inactive. We demonstrated that I1171N/S/T mutations are persistent in an active state and independent of ATP. The I1171S/T mutations showed greater intermolecular H-bonds with ATP than WT-ATP. The molecular mechanics Poisson-Boltzmann surface area analysis revealed that the I1171N/S/T mutation binding energy was similar to that of WT-ATP. This study shows that I1171N/S/T can form stable bonds with ATP and may contribute to a constitutively active kinase. Based on the Y1278-C1097 H-bond and E1167-K1150 salt bridge interaction, I1171N strongly promotes the constitutively active kinase independent of ATP. This structural mechanism study will aid in understanding the oncogenic activity of ALK and the basis for improving the ALK inhibitors.

Computational prognostic evaluation of Alzheimer’s drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches

Drug designing is high-priced and time taking process with low success rate. To overcome this obligation, computational drug repositioning technique is being promptly used to predict the possible therapeutic effects of FDA approved drugs against multiple diseases. In this computational study, protein modeling, shape-based screening, molecular docking, pharmacogenomics, and molecular dynamic simulation approaches have been utilized to retrieve the FDA approved drugs against AD. The predicted MADD protein structure was designed by homology modeling and characterized through different computational resources. Donepezil and galantamine were implanted as standard drugs and drugs were screened out based on structural similarities. Furthermore, these drugs were evaluated and based on binding energy (Kcal/mol) profiles against MADD through PyRx tool. Moreover, pharmacogenomics analysis showed good possible associations with AD mediated genes and confirmed through detail literature survey. The best 6 drug (darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar) further docked and analyzed their interaction behavior through hydrogen binding. Finally, MD simulation study were carried out on these drugs and evaluated their stability behavior by generating root mean square deviation and fluctuations (RMSD/F), radius of gyration (Rg) and soluble accessible surface area (SASA) graphs. Taken together, darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar displayed good lead like profile as compared with standard and can be used as possible therapeutic agent in the treatment of AD after in-vitro and in-vivo assessment.

Implication of Caffeic Acid for the Prevention and Treatment of Alzheimer's Disease: Understanding the Binding with Human Transferrin Using In Silico and In Vitro Approaches.

In present times, a switch from chemical molecules towards natural products is taking place, and the latter is being increasingly explored in the management of diseases due to their broad range of therapeutic potential. Consumption of coffee is thought to reduce Alzheimer's disease (AD); however, the mechanism is still unexplored. Primarily, it is thought that components of coffee are the key players in making it a neuroprotectant. Caffeic acid (CA) is found in high quantities in coffee; thus, it is being increasingly explored to decipher its neuroprotection by various mechanisms. Iron is a toxic element in a free form capable of causing oxidative damage and ultimately contributing to the pathogenesis of AD. Thus, maintaining the proper iron levels is vital and human transferrin (Htf), a glycoprotein, is a key player in this aspect. In this work, we explored the binding mechanism of CA with Htf at the atomistic level, employing molecular docking and extensive molecular dynamics simulation (MD) approaches coupled with spectroscopic techniques in a bid to decipher the mode of interaction of CA with Htf. Molecular docking results demonstrated a strong binding affinity between CA and Htf. Furthermore, MD study highlighted the Htf-CA complex's stability and the ligand's minimal impact on Htf's overall structure. In silico approaches were further backed up by experimental approaches. Strong binding of CA with Htf was ascertained by UV-visible and fluorescence spectroscopy observations. Together, the study provides a comprehensive understanding of the Htf-CA interaction, adding to the knowledge of the use of CA in the treatment of AD, thereby adding another feather to its already known neuroprotective role.

Screening of potent inhibitor from Aquilaria malaccensis Lam. against arachidonic inflammatory enzymes: an insight from molecular docking, ADMET, molecular dynamics simulation and MM-PBSA approaches

The three primary enzymes COX (cyclooxygenase), LOX (lipoxygenase) and CYT-P450 (cytochrome P450), which are part of the arachidonic inflammatory pathway, play crucial role in the development of asthma, rheumatoid arthritis and cardiovascular diseases. Ethnomedicinally, plant-derived chemicals have a major role in the treatment of fatal illnesses. Aquilaria malaccensis Lam. widely known as agarwood is prized for its fragrance and therapeutic properties. The phytochemicals and extracts of this plant have significant healing properties in the treatment of serious illnesses. In the current work, an in-silico approach including molecular docking, ADMET (absorption, distribution, metabolism, excretion and toxicity), molecular dynamics (MD) simulation and molecular mechanics/Poisson–Boltzmann surface area (MM-PBSA) was performed to screen 33 bioactive compounds from this plant against COX-2 and 5-LOX in order to find the most effective inhibitor. 2-(2-Phenylethyl)chromone was found to inhibit both 5-LOX and COX-2, showing the highest binding affinities (−9.1 kcal/mol and −9.0 kcal/mol, respectively) than standard Ibuprofen and nordihydroguaiaretic acid (NDGA). 2-(2-Phenylethyl)chromone showed the highest drug-likeness score and low risk of toxicity compared to other phytochemicals. MD modeling and MM-PBSA calculations showed that 2-(2-Phenylethyl)chromone had a strong persistent binding interaction with 5-LOX than COX-2, and this interaction is comparable to the bounded standards Ibuprofen and NDGA. From this study, we may infer that the 2-(2-Phenylethyl)chromone can serve as a potent inhibitor and has scope to be employed in the treatment of inflammatory ailments. Communicated by Ramaswamy H. Sarma

Temperature Effect on the Deformation Behavior in Nanocrystalline Magnesium under Compression: An Atomistic Study

The classic molecular dynamics (MD) simulation approach has been used to investigate the microstructure change in polycrystalline magnesium (Mg) during compressive deformation at various temperatures. At low temperatures, there exists a competition between the sliding of Shockley partial dislocation (SPD) and perfect <a> dislocation. Abundant dislocation behaviors such as dislocation bundle and double cross slipping are observed. With a temperature increase, the dislocation sliding is hindered by the newly formed grain boundaries (GBs). The grain reorientation should be the compensatory mechanism for plastic deformation at high temperatures. Furthermore, dynamic recrystallization (DRX) is found at the highest temperature investigated. For all the temperature cases studied, twinning is unsensitive against applied compressive stress. The results of this work may help to understand the temperature effect on the mechanism in polycrystalline Mg under compressive deformation.

A Computational Chemistry Approach to the Molecular Design of SiO2 Nanoparticles Coated with Stearic Acid and Sodium Stearate in Ethanol Solvent.

Preparation of hydrophobic SiO2 nanoparticles (NPs) coated with different surfactants is important due to their potential application in different fields of chemistry. In this work, a combined experimental and Molecular Dynamics (MD) simulation approach, is advanced to characterize the adsorption process, in ethanol as a solvent, of stearic acid and sodium stearate on SiO2 spherical NPs with different ionization degrees (0%, 10%, and 23.3%). The main objective is to gain molecular insight into the factors involved in the preparation of hydrophobic coated NPs, which involves the intervention of ion-dipole, electrostatic, and hydrogen bond-type interactions depending on the surfactants and the nature SiO2 NPs. Our results demonstrate that the SiO2 NPs have a good affinity for ethanol solvent medium., as confirmed through the analysis of the Radial Distribution Functions (RDFs)), which indicates that hydrogen bonds are formed at a distance of ∼0.192 nm between ethanol and SiO2 NPs. The presence of Na+ ions reduce the electrostatic repulsion between the -COO- and -SiO- groups in NPs with degrees of ionization of 10% and 23.3%, because it acts as a bridge and thus favors the adsorption between the silanol and carboxylic groups. The investigation of the Potentials of Mean Force (PMFs) suggests that the adsorption on these NPs, is a spontaneous process compared with the case with 0% ionization degree. The experimental coating of the NPs was studied using Atomic Force Microscopy (AFM), a technique that allows the indirect measure of the Work of Adhesion (Wadh), a key quantity to estimate the energy needed to separate the interfaces AFM tip-sample. The experimental values of Wadh for the pure SiO2 NPs and two modified SiO2 NPs correspond to 2.01 J/m2, 1.72 J/m2 and 1.43 J/m2, respectively. The main conclusion is that the interaction energies between surfactants and SiO2 NPs, estimated from MD simulations, and the Wadh obtained from AFM measurements are correlated, in the sense that the reduction in the Wadh, in a solvent-free environment, corresponds to an increment of the interaction energy in the presence of the solvent. This reduction in Wadh is also associated with the fact that the nature of the coating of the SiO2 NPs surfaces increases the NPs hydrophobicity. Our analysis provides a path for the computational design and the prediction of hydrophobicity of coated NPs, which is the main focus of our work.

Theoretical investigation of solvation and inter-chain interactions for phosphate ester dispersants on tetragonal BaTiO3 (0 0 1) in non-aqueous solvents: An ab initio molecular dynamics simulation approach

Tetragonal BaTiO3 is a key material for manufacturing multi-layer ceramic capacitors (MLCCs), and a highly dispersed BaTiO3 suspension, where the surfaces are conjugated by phosphate ester dispersants, is an essential technology for the production of ultra-thin films and small-sized ceramic capacitors. Therefore, understanding the interactions of conjugated polymers with solvents is critical to designing improved dispersants and solvents for commercial MLCC applications. In this work, we theoretically investigate the solvation and inter-chain interactions of mono-alkyl and ethoxy phosphate esters under methanol, ethanol, isopropanol, 1-butanol, and toluene, on tetragonal BaTiO3 (001) using the ab initio molecular dynamics (AIMD) simulations. Our results show that the total number of solvent molecules surrounding mono-alkyl and ethoxy phosphate esters decreases in the order of methanol > ethanol > isopropanol > 1-butanol > toluene, indicating that solvation via van der Waals forces and hydrogen bonding declines with increasing the hydrophobicity of solvent molecules. Also, the solvation interaction energy has a linear correlation with the experimental differential of zeta potential, suggesting that the calculated energy is associated with electrostatic environment at the dispersant/solvent/BaTiO3 interface. Therefore, the solvation interaction energy is an important factor that describes the liquid–solid interfaces as well as a dispersion stability of BaTiO3 suspension.

Hybrid thermo-physical modelling and experimentation of ultrafast laser-based fabrication of polycrystalline core–amorphous shell nitinol nanoparticles

Ultrafast lasers pulses induced ablation of nickel-titanium (NiTi) alloy substrates immersed in deionized water yielded a high-throughput of polycrystalline core - amorphous shell NiTi nanoparticles (NPs) owing to the high pulse energy of femtosecond (fs) lasers. In this study, the alloy NPs were fabricated by varying the laser fluences from 15 to 45 J/cm2. The polycrystalline core - amorphous shell NiTi were confirmed by selected area diffraction patterns via High resolution – Transmission Electron microscopy. Theoretical investigations were carried out via hybrid simulation approach of molecular dynamics simulation and analytical modelling. Molecular dynamics study revealed the spatial and temporal evolution of electron and lattice temperature of NiTi melt pool due to ablation at various laser fluences. The subsequent temporal dynamics of melt-pool temperature along the depth revealed the phase separation via spinodal decomposition process after 40 picoseconds post irradiation of NiTi with ultrafast laser pulse. The analytical modelling incorporating phase explosion theory estimated the thermo-physical expansion of ablated chunks and subsequent fragmentation of NiTi melt pool in liquid–vapor co-existing phase. The parameters of mathematical modelling were evaluated in-conjunction with the experimental results of size distribution of NPs at the laser fluence of 15 J/cm2. Later, the hybrid mathematical model was employed to predict the size of NiTi NPs ablated at higher laser fluences of 30 J/cm2 and 45 J/cm2 and the results were experimentally verified.

Effects of barriers on the thermal enhancement in boiling flow within a ribbed-microchannel using molecular dynamics simulation approach

Effects of barriers on the thermal enhancement in boiling flow within a ribbed-microchannel using molecular dynamics simulation approach

The Molecular Dynamics Simulation of Thermal Properties of R290 for Auto-cascade Refrigeration System

Background: Hydrocarbons are increasingly being considered as potential fourth-generation refrigerants due to their environmentally-friendly properties. However, accurate prediction and calculation of their thermal properties are essential for their industrial application. Objective: In this study, molecular dynamics simulations were performed to calculate the density, self-diffusion coefficient, viscosity and thermal conductivity of R290 at various operating temperatures of 200-240 K and pressures of 0.15 and 0.20 MPa, and 270-390 K and pressures of 1.5 and 2.0 MPa to verify the feasibility of the methods. Methods: The equilibrium molecular dynamics simulation (EMD) approach was utilised. The soundness of the model and force field were verified by calculating the density of the system during the relaxation phase. In the output stage, the self-diffusion coefficient was calculated using the Einstein relation, while the viscosity and thermal conductivity were calculated using the Green-Kubo method. The simulation results were compared with the NIST data values, and the errors were analysed. Results:  Results: The density simulation results for R290 in the relaxation phase yielded an overall average absolute relative deviation (AARD) value of 3.97%. In the output stage, the simulation results for the transport coefficients of R290 showed AARD values of 7.68%, 6.60% and 11.04% for the self-diffusion coefficient, viscosity, and thermal conductivity, respectively, compared to the NIST data values. Conclusion: These results indicate the feasibility of using molecular dynamics simulations to study the transport properties of hydrocarbon refrigerants. The findings also provide a foundation for future research on hydrocarbon refrigerant mixtures. Patent: The research presented in this work could serve as a valuable reference for future patent applications and technological innovations related to hydrocarbon refrigerants, particularly R290. This includes, but is not limited to, delivery pipelines, connectors, storage containers, control and detection systems, and the preparation and application of R290 and other refrigerant mixtures.

Host–guest interactions of Crizotinib with natural and modified cyclodextrins: a combined molecular docking and molecular dynamics simulation approaches

ABSTRACT In this work, molecular docking and molecular dynamics (MD) simulation were applied to investigate the ability of natural cyclodextrins (CDs; Alpha, Beta and Gamma Cyclodextrins) and modified CDs (hydroxypropyl, random methyl and amino Beta Cyclodextrins) to form the stable inclusion complexes (ICs) with Crizotinib, the oral small molecule kinase inhibitor as a chemotropic drug. Results of molecular docking and MD simulation studies demonstrated that Crizotinib forms stable ICs with all natural and modified CDs and in the presence of this drug, all six CDs become more rigid. The presence of Crizotinib and the release of water molecules result in a decrease in the number of hydrogen bonds between cyclodextrins (CDs) and solvent molecules within the encapsulated CDs, compared to the hydrogen bonds observed in free CDs. Additionally, HPBCD exhibited the strongest affinity for binding and established the highest quantity of hydrogen bonds with Crizotinib. Finally, all results of this paper demonstrated the potential of using this formulation to improve the bioavailability of the selected drug.

Water flow rate quantification through an experimental CNT membrane: A molecular dynamics simulation approach

The comprehension of water flow rate within carbon nanostructures holds great importance in both theoretical understanding and engineering design of microscale and nanoscale devices. This study presents a comprehensive numerical model for analyzing the water flow rate in Carbon Nanotube (CNT) membranes. The outcomes of this model have particular relevance in predicting the performance and designing CNT membranes for water desalination, which offer the potential for remarkably rapid transport. By investigating the characteristics of the CNT membrane, various geometric properties that influence the overall flow rate are quantified. Apart from the diameter and length, attention is also given to non-ideal factors associated with the deformation of CNTs from their original structures. Specifically, the impact of eccentricity and bending on the flow rate through CNTs is examined, revealing limited but noteworthy effects. Additionally, a simplified model is developed to characterize the membrane using statistical data pertaining to CNT synthesis. The results of the total water flow rate demonstrate that the existing numerical model closely aligns with the reported experimental values.

Azole-methyl-3-(4-phenoxyphenyl) quinazolin-4(3H) ones, novel quinazoline-azole hybrid scaffolds, as new potent anticancer agents: Design, synthesis, biological evaluation, molecular dynamic simulation and theoretical approach

Herein we describe design and synthesis of new series of small quinazoline molecule connected to the azole moieties. Molecular docking screening were conducted on 102 various hybrids of quinazolinone and azole rings, toward epithelial growth factor receptor (EGFR). Among all screened compounds, six top-ranked hit hybrid scaffolds were finally selected (17a-17f), synthesized and characterized by 1HNMR, 13CNMR and Mass spectroscopy. These molecules have been tested for their antiproliferative activities against two human cancerous cell lines (MCF-7 and A549) as well as normal cell line (MRC-5). Molecular dynamic (MD) simulation were also conducted on these series to show the key drug-target interactions. The results indicated that compound 17b, harboring imidazole moiety, showed strong inhibitory activity with IC50 values of 1.38 ± 0.14 and 5.5 ± 0.09 μΜ against A549 and MCF-7 cell lines, respectively. MD simulation analysis revealed that H-bonds and hydrophobic interactions played an important role in the ligand binding stability.

Molecular bioprospection of Helianthus annuus L. (sunflower) cypselae for antidiabetic therapeutics through network pharmacology, density functional theory and molecular dynamics simulation

Helianthus annuus cypsela (sunflower) is a staple oilseed crop with significant therapeutic applications against diverse diseases including type 2 diabetes mellitus (T2DM). Despite its reported antidiabetic potential, the implicated molecular mechanism of action is yet to be unravelled to date. This study evaluated the molecular mechanism of the antidiabetic activity of sunflower cypsela using network pharmacology (NP), density functional theory, and molecular dynamics (MD) simulation approaches. The six cultivars of sunflower cypsela used were profiled for their secondary metabolites using LC-MS and GC–MS techniques. Subsequently, the genes associated with the identified metabolites were screened against T2DM-associated genes using NP. Based on the KEGG enrichment analysis of the identified common genes, signaling pathways were subsequently identified. The results obtained revealed 87 intersecting genes between the metabolites of sunflower cypsela and T2DM, while the KEGG analysis identified 35 signaling pathways with the PPAR route and its associated genes as the most implicated in T2DM progression with respect to sunflower cypsela. Both MMP1 and PPARA in the PPAR pathways interacted most with the identified metabolites, with CGA (−43.74 kcal/mol), GPA (−41.62 kcal/mol), and CFG (−45.36 kcal/mol) having higher binding free energy than both ROS and MET (reference standards) against MMP1 after 100,000 ps MD simulation. In contrast, ROS (−46.98 kcal/mol) had better affinity against PPARA compared to the top hits of sunflower cypsela. However, against both gene targets, the top hits had significant thermodynamic stability, flexibility, and compactness, which are attributable to their bond interactions and molecular orbital properties. These findings are suggestive of the essential role of the top-hits in the antidiabetic potential of sunflower cypsela through activation of the PPAR signalling pathway and most especially MMP1. In this regard, the modulation of MMP1 and PPARA genes by the identified metabolites of sunflower cypsela may enhance insulin sensitivity and glucose homoeostasis in the management of T2DM.

Insight into novel inhibitors from Sterculia urens against Cholera via pharmacoinformatics and molecular dynamics simulation approaches

The underdeveloped countries with large populations are facing a grave global threat in the form of cholera. Vibrio cholerae, the etiologic agent of Cholera has drawn attention recently due to antimicrobial resistance and resulting outbreaks that necessitates establishment of novel medications to counteract virulence and viability of the pathogen. Sterculia urens Roxb. (Malvaceae) is an ethnomedicinally important tree, which harbors a good number of bioactive phytocompounds. In the present study, 53 phytocompounds of S. urens were screened against the promising target ToxT of V. cholerae employing structure-based drug design approach that revealed three lead compounds, viz., 4,4,5,8-Tetramethylchroman-2-ol (−8.2 kcal/mol), Beta-Bisabolol (−8.2 kcal/mol) and Ledol (−8.7 kcal/mol) with satisfactory ADMET properties. Molecular dynamics simulation for 150 ns unveiled notable compactness and structural stability for the lead compounds considering RMSD, RMSF, Rg, MolSA, PSA and protein-ligand contacts parameters. Molecular mechanics-based MM/GBSA binding energy calculation revealed Beta-Bisabolol (−66.74 kcal/mol) to have better scores than 4,4,5,8-Tetramethylchroman-2-ol (−47.42 kcal/mol) and Ledol (−65.79 kcal/mol). Enzymes were mostly found as drug target class, and Nabilone was found as a structurally similar analog for 4,4,5,8-Tetramethylchroman-2-ol. These discoveries could aid in revealing new antibacterial medications targeting ToxT to combat Cholera. Communicated by Ramaswamy H. Sarma

Structural, optimization of and mechanistic insights into a new thiosemicarbazone derivative as a highly sensitive and selective chemosensor for Hg2+ recognition using DFT, COSMO-RS, RSM, and molecular dynamics simulation approaches

A new thiosemicarbazone derivative, N-(2-hydroxyphenyl)-2-[1-(pyridin-4-yl)ethylidene]hydrazinecarbothioamide (HPEH), has been synthesized, characterized, and further developed as a highly selective and sensitive colorimetric chemosensor for Hg2+ recognition in environmental water samples. Structural conformers of HPEH were successfully identified using a combination of the potential energy surface (PES) and time-dependent density functional theory (TD-DFT) methods. The synthesized HPEH was successfully characterized further and analyzed based on its harmonic vibrational frequencies, NMR spectra, and electronic transitions using the DFT approach. Sigma profiles were generated using the COSMO-RS approach to identify a compatible medium for HPEH to act as a chemosensor. The conditions for the highly sensitive and selective detection of Hg2+ by HPEH were successfully optimized using the statistical response surface methodology approach. The optimum sensing of HPEH occurred in an 8:2 v/v DMSO/pH 7.8 solution at a 20:60 μM HPEH/Hg2+ concentration and after a reaction time of 18 min, with statistically significant independent variables (p < 0.05) for all parameters. Under optimal conditions, the lowest Hg2+ concentration detected by HPEH was 3.56 µM, indicating that HPEH can serve as an alternative and comparable probe for the detection of Hg2+ in aqueous systems. Using the optimized results, the interaction between HPEH and Hg2+ in the chemosensor system was successfully modeled, and the model was subsequently used with the TD-DFT, non-covalent interaction-reduced density gradient (NCI-RDG), and molecular dynamics approaches to gain mechanistic insights into the interaction. The results showed that the newly synthesized HPEH, in addition to being cost-effective, could serve as a suitable alternative and comparable chemosensor for Hg2+ recognition in water samples, with the advantages of being efficient, portable, and eco-friendly, and offering rapid analysis without the need of specialized training.

In-silico Screening of Novel Diterpene Derivatives for their Inhibitory Potentials against MurA Enzyme of Uropathogenic Escherichia coli

background: Enzyme UDP-NAG enolpyruvyl transferase (MurA), which aids in the formation of cell walls and is identified as the primary target of the antibiotic Fosfomycin, is a significant pharmacological target in the case of uropathogenic Escherichia coli (UPEC). Finding a potent drug with a distinct mode of action is required since UPEC treatment is challenging due to resistance and resurrection. methods: Here we have used virtual high-throughput screening and molecular dynamics simulation approach to explore the effectiveness of selected novel Diterpene derivatives against the therapeutic target MurA (both wild type and Cys115Asp mutant, which is responsible for lower effectiveness of Fosfomycin). results: The investigation showed improved binding efficacy of the ligands around the primary active site residue Cys115 as well as enhanced activity against Cys115Asp mutant. Against wildtype receptors, the docking score of best-docked diterpene derivative, DIT1 (-26.18) was found to be much better than that of the known drug, Fosfomycin (-23.72). There were 7 nos of hydrogen bonds formed by DIT1 and 5 nos by Fosfomycin, indicating a stronger interaction of DIT1 with MurA. The mutant form also showed similar findings, suggesting that DIT1 is much more effective than Fosfomycin. conclusion: The above result justifies the potential of Diterpene derivatives in blocking the MurA active site that can prevent peptidoglycan biosynthesis. Effectiveness of DIT1 against wild type as well as Cys115Asp mutant justifies that the selected ligands can be used as suitable drug candidates against MurA to add new molecules in the treatment pipeline. This establishes innovative frameworks for the creation of strong drugs that target MurA after suitable in-vitro and in-vivo trials.