Molecular Dynamics Simulation Approach Research Articles

Computational analysis of mechanical behavior and potential energy of thermoresponsive copper-tantalum nanoalloy.

Temperature, strain rate, and defects are important considerations in determining the mechanical properties of materials. The mechanical properties of nanocrystalline copper-tantalum (Cu-Ta) alloy are investigated using classical molecular dynamics simulation approach in which embedded atom method of potential with periodic boundary conditions in all directions has been adopted. Numerical simulation has been performed to predict the mechanical properties of nanocrystalline copper-tantalum alloy. The virtual tensile test has been conducted at a fixed strain rate and increasing temperature where the discreet change in temperature from 50 to 1600K has been used as a controlling parameter. The strain rate is fixed in the direction of the principal crystallographic planes and has not been affected by the change in temperature. The mechanical properties of the Cu-Ta nanocrystalline alloy such as yield strength, ultimate strength, and Young's modulus are observed. Further, simulations are carried out to analyze the vacancy formation energy with vacancy concentration and potential energy response at discrete temperatures. Nanocrystalline Cu-Ta alloy is observed to be more susceptible to failure at high temperatures. Particularly at 300K, the strength of nanocrystalline Cu-Ta is 6 GPa which decreases to 4 GPa at 1200K.

Exploring the phytochemicals of Platycodon grandiflorus for TMPRSS2 inhibition in the search for SARS-CoV-2 entry inhibitors

Platycodon grandiflorus (Jacq.) A. DC. (Campanulaceae) is commonly known as a balloon flower whose rhizomes have been widely utilized in traditional Chinese medicine (TCM) and in various Japanese prescriptions for the treatment of respiratory diseases, diabetes, and inflammatory disorders. The severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), the causative agent of coronavirusdisease 2019 (COVID-19) global pandemic requires priming of the virus's spike (S) protein by cleavage of the S proteins by a multi-domain type II transmembrane serine protease, transmembrane protease serine 2 (TMPRSS2) to gain entry into the host cell. The current research aims at the screening of active phytocompounds of P. grandiflorus as potential inhibitors of cellular TMPRSS2 using molecular docking and molecular dynamics simulations approach. In silico toxicity analyses show that out of a total of 34 phytocompounds selected for the study, 12 compounds obey Lipinski’s rule of five and have favourable pharmacokinetic properties. The top three lead molecules identified here were Apigenin, Luteolin and Ferulic acid which exhibited binding energies of −7.47 kcal/mol, −6.8 kcal/mol and −6.62 kcal/mol respectively with corresponding inhibition constants of 3.33 µM, 10.39 µM and 13.95 µM. The complexes between the lead molecules and the receptor were held by hydrogen bond interactions with key residues such as Gly383, Gly385, Glu389, Lys390, Asp435, Ser436, Ser441, Cys465 and Lys467, and hydrophobic interactions with surrounding residues. The stability of the protein–ligand complexes was evaluated during 100 ns molecular dynamics (MD) simulation by analysing key geometric properties such as RMSD, RMSF, radius of gyration, total solvent accessible surface area and the number of hydrogen bonds. The binding free energies analysis using MD simulations revealed that the compounds and TMPRSS2 have favourable thermodynamic interactions, which are primarily driven by van der Waals forces. As a result, the selected bioactive phytochemicals from P. grandiflorus that target the cellular TMPRSS2 could offer an alternative treatment option against SARS-CoV-2 infections.

Bisquinoline analogs as corrosion inhibitors for carbon steel in acidic electrolyte: Experimental, DFT, and molecular dynamics simulation approaches

The inhibition performance of two bisquinoline analogs, 3-bis((8-hydroxyquinolin-5-yl)methyl)thiourea (BQMT) and O-((8-hydroxyquinolin-5-yl)methyl)((8-hydroxyquinolin-5-yl)methyl)((8-hydroxyquinolin-5-yl)methyl) carbamothioate (QMHC), on carbon steel (CS) in 1M HCl have been assessed through using weight loss tests, electrochemical techniques, scanning electron microscope (SEM), Uv-visible spectroscopy, as well as theoretical calculations. The experimental outcomes exhibited that BQMT and QMHC have largely inhibited the CS corrosion and their inhibition efficiency enhances with the increase of concentration. The maximum inhibition efficiency of BQMT and QMHC was figured out to be 95.0 and 92.3 percent at 10−3M, respectively. Potentiodynamic polarization (PDP) studies exhibited that BQMT and QMHC behave as mixed-type inhibitors. Adsorption of BQMT and QMHC on CS surface is examined by SEM, Uv-visible, and different isotherm models, which obey Langmuir isotherm. Furthermore, Density functional theory (DFT) and molecular dynamics simulation (MDS) calculations were implemented to understand the corrosion resistance mechanism.

Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors.

Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and 7a and its stereoisomer 13a exhibited excellent activities against Hela cells with IC50 = 0.31 µM and IC50 = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of 7a, a small-scale virtual screen using reverse docking for HDAC isoforms (1–10) was performed and the results showed that HDAC6 was the best receptor for 7a, suggesting that HDAC6 may be a potential target for 7a. The interaction pattern analysis showed that the α-amino amide moiety of 7a coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex’s conformational stability. In this work, we identified 7a as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors.

The interactions between Reactive Black 5 and human serum albumin: combined spectroscopic and molecular dynamics simulation approaches.

Azo dyes are made in significant amounts annually and released into the environment after being employed in the industry. There are some reports about the toxic effects of these dyes on several organisms. Thus, the textile dye Reactive Black 5 (RB5) has been examined for its cytotoxic effects on the human serum albumin (HSA) structure. Molecular interaction between RB5 and HSA indicated the combination of docking methods, molecular dynamic simulation, and multi-spectroscopic approaches. HSA's intrinsic fluorescence was well quenched with enhancing RB5 level, confirming complex formation. Molecular dynamics (MD) simulation was done to study the cytotoxic effects of RB5 and HSA conformation. Molecular modeling revealed that the RB5-HSA complex was stabilized by hydrogen bonds and van der Waals interactions. The results of molecular docking revealed that the binding energy of RB5 to HSA was - 27.94kJ/mol. The change in secondary structure causes the annihilation of hydrogen bonding networks and the reduction of biological activity. This research can indicate a suitable molecular modeling interaction of RB5 and HAS and broaden our knowledge for azo dye toxicity under natural conditions.

Micellization and aggregation approach in aqueous amphiphilic ionic liquid and anionic polymer system

In this study, we investigate the aggregation of an ionic liquid (IL), 1-allyl-3-methylimidazolium bromide ([AMIM][Br]) in aqueous solution containing variable amounts of poly(diallyldimethylammonium) chloride (PDADMAc), using conductivity, density, and viscosity techniques in combination with the molecular dynamics simulation approach. The critical micelle concentration (cmc) after micellization for IL in solutions was derived from the conductivity measurements. The effect of PDADMAc on the physicochemical properties of IL in aqueous solution was investigated using comprehensive biophysical techniques such as UV-visible absorption spectroscopy, viscosity (η) and density (ρ) measurements. With the addition of PDADMAc concentration (0, 0.25, 0.05, and 0.1 g.l-1), cmc values increased due to the interaction between IL and PDADMAc. Our UV spectroscopy results showed that the interaction between PDADMAc and [AMIM][Br] was due to the significant differences in the interactions between the amide group of the polymer, the ionic liquid ions, and the water molecules. The apparent molar volumes (V) were calculated from the experimental densities for the (AMIM)(Br)-PDADMAc systems studied. Viscosity data decreased with increasing IL concentration and increased with [PDADMAc]. A computer simulation was used to investigate the aggregate structure between (AMIM)(Br]) and PDADMAc.

Experimental, molecular docking and molecular dynamic studies of natural products targeting overexpressed receptors in breast cancer.

Natural compounds are proper tools for inhibiting cancer cell proliferation. Hence, the search for these ligands of overexpressed receptors in breast cancer has been a competitive challenge recently and opens new avenues for drug discovery. In this research, we have investigated molecular interactions between natural products and overexpressed receptors in breast cancer using molecular docking and dynamic simulation approaches followed by extraction of the best ligand from Citrus limetta and developing for nanoscale encapsulation composed of soy lecithin using a sonicator machine. The encapsulation process was confirmed by DLS and TEM analyses. Anticancer activity was also examined using MTT method. Among the investigated natural compounds, hesperidin was found to bind to specific targets with stronger binding energy. The molecular dynamics results indicated that the hesperidin-MCL-1 complex is very stable at 310.15 K for 200 ns. The RP-HPLC analysis revealed that the purity of extracted hesperidin was 98.8% with a yield of 1.72%. The results of DLS and TEM showed a strong interaction between hesperidin and lecithin with an entrapped efficiency of 92.02 ± 1.08%. Finally, the cytotoxicity effect of hesperidin was increased against the MDA-MB-231 cell line with an IC50 value of 62.93 μg/mL after encapsulation, whereas no significant effect against the MCF10A cell line. We showed for the first time that hesperidin is a flexible and strong ligand for the MCL-1 receptor. Also, it has the in vitro ability to kill the MDA-MB-231 cell lines without having a significant effect on the MCF10A cell lines. Therefore, hesperidin could be used as a food ingredient to generate functional foods.

25 (S)-Hydroxycholesterol acts as a possible dual enzymatic inhibitor of SARS-CoV-2 Mpro and RdRp–: an insight from molecular docking and dynamics simulation approaches

The coronavirus disease (COVID-19) pandemic has rapidly extended globally and killed approximately 5.83 million people all over the world. But, to date, no effective therapeutic against the disease has been developed. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enters the host cell through the spike glycoprotein (S protein) of the virus. Subsequently, RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) of the virus mediate viral transcription and replication. Mechanistically inhibition of these proteins can hinder the transcription as well as replication of the virus. Recently oxysterols and its derivative, such as 25 (S)-hydroxycholesterol (25-HC) has shown antiviral activity against SARS-CoV-2. But the exact mechanisms and their impact on RdRp and Mpro have not been explored yet. Therefore, the study aimed to identify the inhibitory activity of 25-HC against the viral enzymes RdRp and Mpro simultaneously. Initially, a molecular docking simulation was carried out to evaluate the binding activity of the compound against the two proteins. The pharmacokinetics (PK) and toxicity parameters were analyzed to observe the ‘drug-likeness’ properties of the compound. Additionally, molecular dynamics (MD) simulation was performed to confirm the binding stability of the compound to the targeted protein. Furthermore, molecular mechanics generalized Born surface area (MM-GBSA) was used to predict the binding free energies of the compound to the targeted protein. Molecular docking simulation identified low glide energy −51.0 kcal/mol and −35.0 kcal/mol score against the RdRp and Mpro, respectively, where MD simulation found good binding stability of the compound to the targeted proteins. In addition, the MM/GBSA approach identified a good value of binding free energies (ΔG bind) of the compound to the targeted proteins. Therefore, the study concludes that the compound 25-HC could be developed as a treatment and/or prevention option for SARS-CoV-2 disease-related complications. Although, experimental validation is suggested for further evaluation of the work. Communicated by Ramaswamy H. Sarma

Interaction of Pelargonium sidoides Compounds with Lactoferrin and SARS-CoV-2: Insights from Molecular Simulations.

(1) Background: Pelargonium sidoides extracts and lactoferrin are two important natural, anti-inflammatory, and antiviral agents, which can interfere with the early stages of SARS-CoV-2 infection. Molecular docking and molecular dynamics simulation approaches have been applied to check for the occurrence of interactions of the Pelargonium sidoides compounds with lactoferrin and with SARS-CoV-2 components. (2) Methods: Computational methods have been applied to confirm the hypothesis of a direct interaction between PEL compounds and the lactoferrin protein and between Pelargonium sidoides compounds and SARS-CoV-2 Spike, 3CLPro, RdRp proteins, and membrane. Selected high-score complexes were structurally investigated through classical molecular dynamics simulation, while the interaction energies were evaluated using the molecular mechanics energies combined with generalized Born and surface area continuum solvation method. (3) Results: Computational analyses suggested that Pelargonium sidoides extracts can interact with lactoferrin without altering its structural and dynamical properties. Furthermore, Pelargonium sidoides compounds should have the ability to interfere with the Spike glycoprotein, the 3CLPro, and the lipid membrane, probably affecting the functional properties of the proteins inserted in the double layer. (4) Conclusion: Our findings suggest that Pelargonium sidoides may interfere with the mechanism of infection of SARS-CoV-2, especially in the early stages.

Challenges and limits of mechanical stability in 3D direct laser writing

Direct laser writing is an effective technique for fabrication of complex 3D polymer networks using ultrashort laser pulses. Practically, it remains a challenge to design and fabricate high performance materials with different functions that possess a combination of high strength, substantial ductility, and tailored functionality, in particular for small feature sizes. To date, it is difficult to obtain a time-resolved microscopic picture of the printing process in operando. To close this gap, we herewith present a molecular dynamics simulation approach to model direct laser writing and investigate the effect of writing condition and aspect ratio on the mechanical properties of the printed polymer network. We show that writing conditions provide a possibility to tune the mechanical properties and an optimum writing condition can be applied to fabricate structures with improved mechanical properties. We reveal that beyond the writing parameters, aspect ratio plays an important role to tune the stiffness of the printed structures.

Antibodies Against Phosphorylcholine Among 60-Year-Olds: Clinical Role and Simulated Interactions.

AimsAntibodies against phosphorylcholine (anti-PC) are implicated as protection markers in atherosclerosis, cardiovascular disease (CVD), and other chronic inflammatory conditions. Mostly, these studies have been focused on IgM. In this study, we determined IgG, IgG1, and IgG2 anti-PC among 60-year-olds.MethodsBased on a 7-year follow-up of 60-year-olds (2,039 men and 2,193 women) from Stockholm County, we performed a nested case-control study of 209 incident CVD cases with 620 age- and sex-matched controls. Anti-PC was determined using ELISA. We predicted the binding affinity of PC with our fully human, in-house-produced IgG1 anti-PC clones (i.e., A01, D05, and E01) using the molecular docking and molecular dynamics simulation approach, to retrieve information regarding binding properties to PC.ResultsAfter adjustment for confounders, IgG and IgG2 anti-PC showed some significant associations, but IgG1 anti-PC was much stronger as a protection marker. IgG1 anti-PC was associated with an increased risk of CVD below 33rd, 25th, and 10th percentile and of stroke below 33rd and 25th, and of myocardial infarction (MI) below 10th percentile. Among men, a strong association with stroke was determined below the 33rd percentile [HR 9.20, CI (2.22–38.12); p = 0.0022]. D05 clone has higher binding affinity followed by E01 and A01 using molecular docking and further have been confirmed during the course of 100 ns simulation. The stability of the D05 clone with PC was substantially higher.ConclusionIgG1 anti-PC was a stronger protection marker than IgG anti-PC and IgG2 anti-PC and also separately for men. The molecular modeling approach helps in identifying the intrinsic properties of anti-PC clones and atomistic interactions with PC.

Identification of Putative Elicitors From Plant Root Exudates Responsible for PsoR Activation in Plant-Beneficial Pseudomonas spp. by Docking and Molecular Dynamics Simulation Approaches to Decipher Plant-Microbe Interaction.

Plants and rhizobacteria are coexisting since the beginning, but the exact mechanism of communication between them remains enigmatic. The PsoR protein of plant-beneficial Pseudomonas spp., a group of root-associated bacteria, is known to produce a range of antifungal and insecticidal secondary metabolites like 2,4-diacetyl phloroglucinol (DAPG), pyrrolnitrin, and chitinase making them great biocontrol agents and thus helping in plant growth promotion. To better understand the inter-kingdom signaling between plants and plant growth-promoting rhizobacteria (PGPR), the interaction of PsoR with various root exudates was investigated computationally. For this, we first modeled the PsoR protein and confirmed it using the Ramachandran plot. A total of 59 different low molecular weight phytochemicals, secreted as root exudates by plants, were identified by extensive text mining. They were virtually screened with the PsoR protein by molecular docking. Based on the lowest binding energy, ranging from −7.1 to −6.3 kcal mol−1, the top five exudates were chosen. To analyze the stability of the docked protein–ligand complex, a molecular dynamics (MD) simulation of 100 nanoseconds was done. Two root exudates, saponarin and 2-benzoxazolinone (BOA), showed suitable binding with PsoR by forming hydrogen, hydrophobic, and Van der Waals interactions. To confirm the MD simulation results, RMSF, RG, SASA, and interaction energy were calculated. This computational study first time reports that saponarin and 2-BOA, predominantly present in the root exudates of barley and wheat, respectively, demonstrate effective binding with the modeled PsoR protein and are likely of showing cross-kingdom interactions.

Exploring the antihyperglycemic potential of tetrapeptides devised from AdMc1 via different receptor proteins inhibition using in silico approaches.

Introduction:Diabetes mellitus is a heterogenous group of chronic metabolic disorders that results due to deficiency in insulin secretion and signalling. Multiple factors held responsible for onset of diabetes due to defects in glucose metabolism and cellular signalling mechanism. Over the past few years, many plant derived bioactive compounds have been recorded with increased efficacy and fewer side-effects against variety of diseases.Methods:In the current study, molecular docking and molecular dynamics simulation approaches were employed to evaluate the tetrapeptides devised from AdMc1 protein of Momordica charantia. Due to unavailability of appropriate template for modelling of 3D structure of AdMc1 protein, I-TASSER server was employed for prediction of good quality tertiary structure. Predicted model was refined by GalaxyRefine Web and evaluated by Verify 3D, ERRAT and Ramachandran plot analysis. Next, a ready-to-dock library of fifty tetrapeptides as potent inhibitors was prepared and docked against aldose reductase (AR), protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, α-amylase and glycogen synthase kinase 3-beta as receptor proteins. Molecular dynamics (MD) simulation was performed on Schrodinger’s Desmond Module to check stability of the best docking complex.Results:Top five ligands were selected against each receptor protein based on their binding pattern and docking scores. Among selected ligands (i.e. VEID, TVEV, AYAY, EEIA, ITTV, TTIT, LPSM, RGIE, TTVE and EIAR) followed all parameters in drug scanning and ADMET screening tests. The MD simulations confirmed that the best selected peptide (i.e. VEID) docked with AR and PTP1B was structurally stable.Conclusion:In the light of overall results of all analyses employed in this study, the selected ligands could be further processed as potential hypoglycaemic drug candidates.

Genome sequencing and in silico analysis of isoprene degrading monooxygenase enzymes of Sphingobium sp. BHU LFT2

The whole genome sequencing of a novel isoprene degrading strain of Sphingobium sp. BHU LFT2, its in silico analysis for identifying and characterizing enzymes, especially isoprene monooxygenases (IsoMO), which initiate the degradation process, and in vitro validation with cell extract of optimal temperature and pH and analysis for utilizing isoprene as the preferential substrate, were conducted. The most efficient monooxygenase was identified through comparative analyses using molecular docking followed by molecular dynamics simulation approach. The in silico results revealed high thermostability for most of the monooxygenases. Most potent monooxygenase with locus ID JQK15_20300 exhibiting high sequence similarity with known monooxygenases of isoprene-degrading Rhodococcus sp. LB1 and SC4 strains was identified. Interaction energy of −17.25 kJ/mol for JQK15_20300 with isoprene, was almost similar as that analysed for above-mentioned similar known counterparts, was exhibited by the molecular docking. Molecular dynamic simulation of 100 ns and free energy analysis of JQK15_20300 in the complex with isoprene gave persistent interaction of isoprene with JQK15_20300 during the simulation with high average binding energy of −47.13 kJ/mol thus proving higher affinity of JQK15_20300 for isoprene. The study revealed that the highly efficient isoprene degrading strain of Sphingobium sp. BHU LFT2 having effective monooxygenase could be utilized for large-scale applications including detoxification of air contaminated with isoprene in closed working systems. Communicated by Ramaswamy H. Sarma

Identification of Zinc-Binding Inhibitors of Matrix Metalloproteinase-9 to Prevent Cancer Through Deep Learning and Molecular Dynamics Simulation Approach.

The overexpression of matrix metalloproteinase-9 (MMP-9) is associated with tumor development and angiogenesis, and hence, it has been considered an attractive drug target for anticancer therapy. To assist in drug design endeavors for MMP-9 targets, an in silico study was presented to investigate whether our compounds inhibit MMP-9 by binding to the catalytic domain, similar to their inhibitor or not. For that, in the initial stage, a deep-learning algorithm was used for the predictive modeling of the CHEMBL321 dataset of MMP-9 inhibitors. Several regression models were built and evaluated based on R2, MAE MSE, RMSE, and Loss. The best model was utilized to screen the drug bank database containing 9,102 compounds to seek novel compounds as MMP-9 inhibitors. Then top high score compounds were selected for molecular docking based on the comparison between the score of the reference molecule. Furthermore, molecules having the highest docking scores were selected, and interaction mechanisms with respect to S1 pocket and catalytic zinc ion of these compounds were also discussed. Those compounds, involving binding to the catalytic zinc ion and the S1 pocket of MMP-9, were considered preferentially for molecular dynamics studies (100 ns) and an MM-PBSA (last 30 ns) analysis. Based on the results, we proposed several novel compounds as potential candidates for MMP-9 inhibition and investigated their binding properties with MMP-9. The findings suggested that these compounds may be useful in the design and development of MMP-9 inhibitors in the future.

Targeting the HIV-1 Tat and Human Tat Protein Complex through Natural Products: An In silico Docking and Molecular Dynamics Simulation Approach

Targeting the HIV-1 Tat and Human Tat Protein Complex through Natural Products: An In silico Docking and Molecular Dynamics Simulation Approach

Computational screening and analysis of deleterious nsSNPs in human p14ARF (CDKN2A gene) protein using molecular dynamic simulation approach

Cyclin-dependent kinase inhibitor 2 A (CDKN2A) gene belongs to the cyclin-dependent kinase family that code for two transcripts (p16INK4A and p14ARF), both work as tumor suppressors proteins. The mutation that occurs in the p14ARF protein can lead to different types of cancers. Single nucleotide polymorphisms (SNPs) are an important type of genetic alteration that can lead to different types of diseases. In this study, we applied the computational strategy on human p14ARF protein to identify the potential deleterious nsSNPs and check their impact on the structure, function, and protein stability. We applied more than ten prediction tools to screen the retrieved 288 nsSNPs, consequently extracting four deleterious nsSNPs i.e., rs139725688 (R10G), rs139725688 (R21W), rs374360796 (F23L) and rs747717236 (L124R). Homology modeling, conservation and conformational analysis of mutant models were performed to examine the divergence of these variants from the native p14ARF structure. All-atom molecular dynamics simulation revealed a significant impact of these mutations on protein stability, compactness, globularity, solvent accessibility and secondary structure elements. Protein-protein interactions indicated that p14ARF operates as a hub linking clusters of different proteins and that changes in p14ARF may result in the disassociation of numerous signal cascades. Our current study is the first survey of computational analysis on p14ARF protein that determines the association of these nsSNPs with the altered function of p14ARF protein and leads to the development of various types of cancers. This research proposes the described functional SNPs as possible targets for proteomic investigations, diagnostic procedures, and treatments. Communicated by Ramaswamy H. Sarma.

A Perspective for Ménière's Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2.

Ménière’s disease is a chronic illness characterized by intermittent episodes of vertigo associated with fluctuating sensorineural hearing loss, tinnitus and aural pressure. This pathology strongly correlates with a dilatation of the fluid compartment of the endolymph, so-called hydrops. Dexamethasone is one of the therapeutic approaches recommended when conventional antivertigo treatments have failed. Several mechanisms of actions have been hypothesized for the mode of action of dexamethasone, such as the anti-inflammatory effect or as a regulator of inner ear water homeostasis. However, none of them have been experimentally confirmed so far. Aquaporins (AQPs) are transmembrane water channels and are hence central in the regulation of transcellular water fluxes. In the present study, we investigated the hypothesis that dexamethasone could impact water fluxes in the inner ear by targeting AQP2. We addressed this question through molecular dynamics simulations approaches and managed to demonstrate a direct interaction between AQP2 and dexamethasone and its significant impact on the channel water permeability. Through compartmentalization of sodium and potassium ions, a significant effect of Na+ upon AQP2 water permeability was highlighted as well. The molecular mechanisms involved in dexamethasone binding and in its regulatory action upon AQP2 function are described.

The Molecular Basis of the Effect of Temperature on the Structure and Function of SARS-CoV-2 Spike Protein

The remarkable rise of the current COVID-19 pandemic to every part of the globe has raised key concerns for the current public healthcare system. The spike (S) protein of SARS-CoV-2 shows an important part in the cell membrane fusion and receptor recognition. It is a key target for vaccine production. Several researchers studied the nature of this protein under various environmental conditions. In this work, we applied molecular modeling and extensive molecular dynamics simulation approaches at 0°C (273.15 K), 20°C (293.15 K), 40°C (313.15 K), and 60°C (333.15 K) to study the detailed conformational alterations in the SARS-CoV-2 S protein. Our aim is to understand the influence of temperatures on the structure, function, and dynamics of the S protein of SARS-CoV-2. The structural deviations, and atomic and residual fluctuations were least at low (0°C) and high (60°C) temperature. Even the internal residues of the SARS-CoV-2 S protein are not accessible to solvent at high temperature. Furthermore, there was no unfolding of SARS-CoV-2 spike S reported at higher temperature. The most stable conformations of the SARS-CoV-2 S protein were reported at 20°C, but the free energy minimum region of the SARS-CoV-2 S protein was sharper at 40°C than other temperatures. Our findings revealed that higher temperatures have little or no influence on the stability and folding of the SARS-CoV-2 S protein.

Computational Identification of Druggable Bioactive Compounds from Catharanthus roseus and Avicennia marina against Colorectal Cancer by Targeting Thymidylate Synthase.

Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.