SOx Functionalized NiOOH Nanosheets Embedded in Ni(OH)2 Microarray for High-Efficiency Seawater Oxidation.

A nano-micro heterostructure has been established to address the challenges of selectivity, stress, pitting corrosion, and long-term durability of anodes in unpurified seawater. The heterostructure comprised NiOOH nanosheets embedded within a high surface area Ni(OH)2 microarray, and the surface structure is further functionalized with sulfate (SOx ). This cation-selective protective layer impedes chloride (Cl- ) diffusion and abstracts H from reaction intermediates, leading to enhanced selectivity and corrosion resistance of the anode. The multilevel porosity within the randomly oriented nanosheets and the underlying support provide short diffusion channels for ions and mass migration, ensuring efficient ion transport and long-term structural and mechanical durability of the active sites, even at high current density. Remarkably, the catalyst requires a small input voltage of 400 mV to deliver a current density of 1 A cm-2 and maintains it for over 168 h without noticeable degradation or hypochlorite formation. Spectroscopic analysis and density functional theory (DFT) calculations reveal that the Ni electronic structure in the +3 valence state, its strong structural interaction with the underlying microarray, and the functionality of SOx significantly reduce the required potential for O-O coupling.

Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets.

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein-drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-021-01843-0.

Physicochemical stability study of protein-benzoic acid complexes using molecular dynamics simulations.

Carboxyl-modified substrates are the most common chemical moieties that are frequently used as protein defibrillators. We studied the stability of protein-benzoic acid complexes with bovine serum albumin (BSA), zein and lysozyme proteins using various computational methods. Structural model for zein was built using homology modelling technique and molecular docking was used to prepare complex structures of all three proteins with benzoic acid. Molecular dynamics calculations performed on these complex structures provided a strong support for the stability of protein-benzoic acid complexes. The results from various analyses including root-mean-square deviation (RMSD) and radius of gyration showed the stability and compactness of all proteins-benzoic acid complexes. Moreover, exploration of structural fluctuations in proteins revealed the stability of active site residues. Two potential binding modes of benzoic acid with all three proteins were identified via cluster analysis. The binding mode which was retrieved from top cluster containing 86-91% of total conformations displayed very strong binding interactions for zein, BSA and lysozyme proteins. In addition, the results of binding mode showed that various interactions, including hydrogen binding, hydrophobic and electrostatic interactions were important for the optimal binding of benzoic acid with the active sites of proteins. Exploration of solvent accessible surface area showed that lysozyme-binding cavity was more exposed to the surface as compared to the other two proteins. Free energy analysis of all protein systems showed the stability of protein-benzoic acid complexes with lysozyme and BSA relatively more stable than zein system. The results of our study provided important insights to the dynamic and structural information about protein-benzoic acid interactions with BSA, zein and lysozyme proteins. This work is important in enhancing the stability of therapeutic protein drugs loaded on carboxyl substrates.

Secondary Structural Changes in Proteins as a Result of Electroadsorption at Aqueous-Organogel Interfaces.

The electroadsorption of proteins at aqueous-organic interfaces offers the possibility to examine protein structural rearrangements upon interaction with lipophilic phases, without modifying the bulk protein or relying on a solid support. The aqueous-organic interface has already provided a simple means of electrochemical protein detection, often involving adsorption and ion complexation; however, little is yet known about the protein structure at these electrified interfaces. This work focuses on the interaction between proteins and an electrified aqueous-organic interface via controlled protein electroadsorption. Four proteins known to be electroactive at such interfaces were studied: lysozyme, myoglobin, cytochrome c, and hemoglobin. Following controlled protein electroadsorption onto the interface, ex situ structural characterization of the proteins by FTIR spectroscopy was undertaken, focusing on secondary structural traits within the amide I band. The structural variations observed included unfolding to form aggregated antiparallel ß-sheets, where the rearrangement was specifically dependent on the interaction with the organic phase. This was supported by MALDI ToF MS measurements, which showed the formation of protein-anion complexes for three of these proteins, and molecular dynamic simulations, which modeled the structure of lysozyme at an aqueous-organic interface. On the basis of these findings, the modulation of protein secondary structure by interfacial electrochemistry opens up unique prospects to selectively modify proteins.

Computational site-directed mutagenesis studies of the role of the hydrophobic triad on substrate binding in cholesterol oxidase.

Cholesterol oxidase (ChOx) is a flavoenzyme that oxidizes and isomerizes cholesterol (CHL) to form cholest-4-en-3-one. Molecular docking and molecular dynamics simulations were conducted to predict the binding interactions of CHL in the active site. Several key interactions (E361-CHL, N485-FAD, and H447-CHL) were identified and which are likely to determine the correct positioning of CHL relative to flavin-adenine dinucleotide (FAD). Binding of CHL also induced changes in key residues of the active site leading to the closure of the oxygen channel. A group of residues, Y107, F444, and Y446, known as the hydrophobic triad, are believed to affect the binding of CHL in the active site. Computational site-directed mutagenesis of these residues revealed that their mutation affects the conformations of key residues in the active site, leading to non-optimal binding of CHL and to changes in the structure of the oxygen channel, all of which are likely to reduce the catalytic efficiency of ChOx. Proteins 2017; 85:1645-1655. © 2017 Wiley Periodicals, Inc.

Finding off-targets, biological pathways, and target diseases for chymase inhibitors via structure-based systems biology approach.

Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors.

Sensing of volatile pollutants on reduced graphene oxide-polypyrrole composite: DFT investigation.

Air pollutants generated from volatile toxic chemicals pose significant public health concerns. Density functional theory (DFT) computations were used in this research to explore the efficiency and mechanism of harmful gas sensing over the reduced graphene oxide-polypyrrole (rGO-PPy) composite. Volatile molecule sensing was investigated for the NH3, H2CO, CH3OH, and C2H5OH gas molecules over three PPy orientations on the rGO substrate. Results showed that PPy orientation over rGO plays a crucial role in the sensing efficiency of the investigated gas molecules. The rGO-PPy composite, with PPy in a vertical orientation, demonstrated higher stability and enhanced sensing than other orientations. The results indicate that the strong hydrogen bonding of NH3 and CH3OH with both PPy and rGO significantly enhanced the sensing of these gas molecules on rGO by influencing the charge transfer with adsorption energy values of - 0.84 and - 0.92 eV, respectively. The lack of a direct hydrogen bonding with rGO and the weak hydrogen bonding with PPy caused a weak adsorption of H2CO and C2H5OH over rGO as indicated by the adsorption energy values of - 0.60 and - 0.78 eV, respectively. Selectivity analysis for the NH3 and C2H5OH gas molecules showed that NH3 can maintain hydrogen bonding with PPy in the presence of C2H5OH while C2H5OH cannot sustain this interaction. This study highlights the importance of the structural and electronic properties of the rGO-PPy composite in volatile pollutant sensing, providing insights for designing high-performance gas sensors.

Recent Advances on Metal Oxide Based Sensors for Environmental Gas Pollutants Detection.

Optimizing materials and associated structures for detecting various environmental gas pollutant concentrations has been a major challenge in environmental sensing technology. Semiconducting metal oxides (SMOs) fabricated at the nanoscale are a class of sensor technology in which metallic species are functionalized with various dopants to modify their chemiresistivity and crystalline scaffolding properties. Studies focused on recent advances of gas sensors utilizing metal oxide nanostructures with a special emphasis on the structure-surface property relationships of some typical n-type and p-type SMOs for efficient gas detection are presented. Strategies to enhance the gas sensor performances are also discussed. These oxide material sensors have several advantages such as ease of handling, portability, and doped-based SMO sensing detection ability of environmental gas pollutants at low temperatures. SMO sensors have displayed excellent sensitivity, selectivity, and robustness. In addition, the hybrid SMO sensors showed exceptional selectivity to some CWAs when irradiated with visible light while also displaying high reversibility and humidity independence. Results showed that TiO2 surfaces can sense 50 ppm SO2 in the presence of UV light and under operating temperatures of 298-473 K. Hybrid SMO displayed excellent gas sensing response. For example, a CuO-ZnO nanoparticle network of a 4:1 vol.% CuO/ZnO ratio exhibited responses three times greater than pure CuO sensors and six times greater than pure ZnO sensors toward H2S. This review provides a critical discussion of modified gas pollutant sensing capabilities of metal oxide nanoparticles under ambient conditions, focusing on reported results during the past two decades on gas pollutants sensing.

Orbital interaction and electron density transfer in PdII([9]aneB2A)L2 complexes: theoretical approaches.

The geometric structures of Pd-complexes {Pd([9]aneB2A)L2 and Pd([9]aneBAB)L2 where A = P, S; B = N; L = PH3, P(CH3)3, Cl-}, their selective orbital interaction towards equatorial or axial (soft A…Pd) coordination of macrocyclic [9]aneB2A tridentate to PdL2, and electron density transfer from the electron-rich trans L-ligand to the low-lying unfilled a1g(5s)-orbital of PdL2 were investigated using B3P86/lanl2DZ for Pd and 6-311+G** for other atoms. The pentacoordinate endo-[Pd([9]aneB2A)(L-donor)2]2+ complex with an axial (soft A--Pd) quasi-bond was optimized for stability. The fifth (soft A--Pd) quasi-bond between the σ-donor of soft A and the partially unfilled a1g(5s)-orbital of PdL2 was formed. The pentacoordinate endo-Pd([9]aneB2A)(L-donor)2]2+ complex has been found to be more stable than the corresponding tetracoordinate endo-Pd complexes. Except for the endo-Pd pentacoordinates, the tetracoordinate Pd([9]aneBAB)L2 complex with one equatorial (soft A-Pd) bond is found to be more stable than the Pd([9]aneB2A)L2 isomer without the equatorial (A-Pd) bond. In particular, the geometric configuration of endo-[Pd([9]anePNP)(L-donor)2]2+ could not be optimized.

Doping matters in carbon nanomaterial efficiency in environmental remediation.

Carbon nanomaterials (CNMs) are rapidly emerging in materials science research due to their widespread environmental applications. They are useful for environmental pollutants' remediation through various methods. Heteroatom doping resulted in reliable approaches to overcome pristine CNMs challenges. The engineering of the dopants is believed to be a promising route to improve the efficiency of CNMs in environmental remediation. The idea of doping has been attractive since it allows the control of electronic properties due to the electron transfer between dopants and the host material and the dopants along with the bonding between analogous atoms and carbon atoms. This mini-review, through computational and experimental studies, puts special emphasis on the role of doping different CNMs as an efficient approach to enhance the environmental remediation.

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors.

BACKGROUND: Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study. METHODS: Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features. RESULTS: The best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors. CONCLUSION: A quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were identified to be used in designing novel and future renin inhibitors as antihypertensive drugs.

3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors.

Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating "Hypo1", it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC(50)) data thus successfully validating "Hypo1" by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors.

Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter.

The human ATP-binding cassette B5 (ABCB5) transporter, a member of the ABC transporter superfamily, is linked to chemoresistance in tumour cells by drug effluxion. However, little is known about its structure and drug-binding sites. In this study, we generated an atomistic model of the full-length human ABCB5 transporter with the highest quality using the X-ray crystal structure of mouse ABCB1 (Pgp1), a close homologue of ABCB5 and a well-studied member of the ABC family. Molecular dynamics simulations were used to validate the atomistic model of ABCB5 and characterise its structural properties in model cell membranes. Molecular docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide were then used to identify at least three putative binding sites for chemotherapeutic drugs transported by ABCB5. The location of these three binding sites is predicted to overlap with the corresponding binding sites in Pgp1. These findings will serve as the basis for future in vitro studies to validate the nature of the identified substrate-binding sites in the full-length ABCB5 transporter.

Lysozyme and Human Serum Albumin Proteins as Potential Nitric Oxide Cardiovascular Drug Carriers: Theoretical and Experimental Investigation.

Nitric oxide-containing drugs present a critical remedy for cardiovascular diseases. Nitroglycerin (NG, O-NO) and S-nitrosoglutathione (SNG, S-NO) are the most common nitric oxide drugs for cardiovascular diseases. Insights regarding the binding affinity of NO drugs with lysozyme and human serum albumin (HSA) proteins and their dissociation mechanism will provide inquisitive information regarding the potential of the proteins as drug carriers. For the first time, the binding interactions and affinities are investigated using molecular docking, conventional molecular dynamics, steered molecular dynamics, and umbrella sampling to explore the ability of both proteins to act as nitric oxide drug carriers. The molecular dynamics simulation results showed higher stability of lysozyme-drug complexes compared to HSA. For lysozyme, cardiovascular drugs were bound in the protein cavity mainly by the electrostatic and hydrogen bond interactions with residues ASP53, GLN58, ILE59, ARG62, TRP64, ASP102, and TRP109. For HSA, key binding residues were ARG410, TYR411, LYS414, ARG485, GLU450, ARG486, and SER489. The free energy profiles produced from umbrella sampling also suggest that lysozyme-drug complexes had better binding affinity than HSA-drug. Binding characteristics of nitric oxide-containing drugs NG and SNG to lysozyme and HSA proteins were studied using fluorescence and UV-vis absorption spectroscopy. The relative change in the fluorescence intensity as a function of drug concentrations was analyzed using Stern-Volmer calculations. This was also confirmed by the change in the UV-vis spectra. Fluorescence quenching results of both proteins with the drugs, based on the binding constant values, demonstrated significantly weak binding affinity to NG and strong binding affinity to SNG. Both computational and experimental studies provided important data for understanding protein-drug interactions and will aid in developing potential drug carrier systems in cardiovascular diseases.

Characterization of Protein-Facilitated Ion-Transfer Mechanism at a Polarized Aqueous/Organic Interface.

Protein electrochemistry studies at a polarized interface between two immiscible electrolyte solutions (ITIES) indicate that the detection mechanism of a protein at the interface involves a combination of protein-anion complexation and interfacial adsorption processes. A detailed characterization of the protein-facilitated mechanism of ion transfer at the ITIES will allow the development of new label-free biomolecular detection tools. Molecular dynamics simulations were performed to describe the mechanism of transfer of the hydrophobic anion tetraphenylborate (TPB-) from a 1,2-dichloroethane (organic) phase to an aqueous phase mediated by lysozyme as a model protein under the action of an external electric field. The anion migrated to the protein at the interface and formed multiple contacts. The side chains of positively charged Lys and Arg residues formed electrostatic interactions with the anion. Nonpolar residues like Trp, Met, and Val formed hydrophobic contacts with the anion as it moved along the protein surface. During this process, lysozyme adopted multiple, partially unfolded conformations at the interface, all involving various anion-protein complexes with small free-energy barriers between them. The general mechanism of protein-facilitated ion transfer at a polarized liquid-liquid interface thus likely involves the movement of a hydrophobic anion along the protein surface through a combination of electrostatic and hydrophobic interactions.

Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.

A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).

Green and cytocompatible carboxyl modified gold-lysozyme nanoantibacterial for combating multidrug-resistant superbugs.

The dissemination of multi-drug resistant (MDR) superbugs in hospital environments, communities and food animals and the very dynamic bacterial mutation frequency require the development of prolonged therapeutic strategies to gain mastery over antibiotic resistance. A AuNP-lysozyme nanoantibacterial was fabricated by the conjugation of AuNPs-C6H4-4-COOH with lysozyme via green reduction of aryldiazonium gold(iii) salt [HOOC-4-C6H4N[triple bond, length as m-dash]N]AuCl4. Results from molecular docking calculations aimed at revealing the binding mode of benzoic acid with the lysozyme structure clearly showed the lowest energy conformation with benzoic acid bound in the deep buried hydrophobic cavity of the protein active site through strong hydrogen bonding and hydrophobic interactions, thus validating the experimental outcomes of the current study which also exhibited the binding of -COOH functional groups in the interior of the protein structure. The superiority of the lysozyme bioconjugate against superbugs was demonstrated by the enhanced and broadened lysozyme antibacterial activities of 98-99% against extended spectrum beta lactamase (ESBL) producing Escherichia coli and imipenem-resistant Pseudomonas aeruginosa clinical isolates and a selection of Gram-negative and Gram-positive standard ATCC strains. Selective toxicity against bacteria was confirmed by the high viability of HeLa and fibroblast cell lines and the outstanding hemocompatibility at the minimum bacterial inhibitory concentrations (MICs). Turbidimetric enzyme kinetic assay showed the enhancement of the lysozyme hydrolytic activity by gold nanoparticles on the Micrococcus lysodeikticus bacterial substrate. Using gel electrophoresis, the induced cell wall breakdown was confirmed by detecting the leaked-out bacterial genomic DNA. The integrity and morphology changes of the E. coli bacteria were investigated using a scanning electron microscope after one hour of contact with the lysozyme-gold bioconjugate. The antibacterial functionalities showed little or no damage to healthy human cells and can be applied to wound dressings and medical devices.

Erdheim-Chester disease associated with a novel, complex BRAF p.Thr599_Val600delinsArgGlu mutation.

BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim-Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599_Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.

Adsorption and Unfolding of Lysozyme at a Polarized Aqueous-Organic Liquid Interface.

The adsorption of proteins at the interface between two immiscible electrolyte solutions has been found to be key to their bioelectroactivity at such interfaces. Combined with interfacial complexation of organic phase anions by cationic proteins, this adsorption process may be exploited to achieve nanomolar protein detection. In this study, replica exchange molecular dynamics simulations have been performed to elucidate for the first time the molecular mechanism of adsorption and subsequent unfolding of hen egg white lysozyme at low pH at a polarized 1,2-dichloroethane/water interface. The unfolding of lysozyme was observed to occur as soon as it reaches the organic-aqueous interface, which resulted in a number of distinct orientations at the interface. In all cases, lysozyme interacted with the organic phase through regions rich in nonpolar amino acids, such that the side chains are directed toward the organic phase, whereas charged and polar residues were oriented toward the aqueous phase. By contrast, as expected, lysozyme in neat water at low pH does not exhibit significant structural changes. These findings demonstrate the key influence of the organic phase upon adsorption of lysozyme under the influence of an electric field, which results in the unfolding of its structure.

Binding mode analyses and pharmacophore model development for stilbene derivatives as a novel and competitive class of α-glucosidase inhibitors.

Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.