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Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors. [ABSTRACT FROM AUTHOR]

The impact of solute Al on the penetration of Cu atoms into the Fe grain boundary (GB) in the Fe–Cu embrittlement system was investigated by performing molecular dynamics simulations. Furthermore, the first principle density functional theory calculation was also employed to determine the binding properties and the electronic structure of GBs doped with solute atoms. The inhibition mechanism of liquid metal embrittlement (LME) cracks in the Fe–Cu system by Al was analyzed at the atomic scale by conducting simulations and calculations. The results show that the diffusion rate of Al along with the GB direction was much higher than that of Cu, and the preferential penetration and segregation of Al atoms acted as a barrier layer. Moreover, the addition of Al reduced the potential energy of Cu atoms, thus stabilizing their motion. These factors significantly inhibited the diffusion of Cu atoms along with the GB direction. The binding property of Fe GB doped with a high concentration of Cu was severely deteriorated, while the Al doping improved the atomic bonding. GBs with higher binding properties are less susceptible to fracture and groove under the application of tensile stress. This paper presents a novel perspective on the inhibition mechanism of LME cracks by doping a third component to inhibit the penetration of embrittlement atoms. [ABSTRACT FROM AUTHOR]

COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • All 34 compounds were evaluated for their anti-HBV activity and cytotoxicity. • Compound 7b (EC 50 = 0.83 ± 0.33 µM) displayed comparable anti-HBV activity to NVR3-778 (EC 50 = 0.73 ± 0.20 µM). • Compound 7b (328.8 µg/mL, pH 7) displayed better solubility than NVR 3-778 (35.8 µg/mL, pH 7) as designed. • Size exclusion chromatography and quantification of encapsidated RNA were performed to investigate the antiviral mechanism. • Molecular dynamics simulation was conducted to understand key interactions of novel derivatives with the binding pocket. Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC 50 = 0.83 ± 0.33 µM, CC 50 = 19.4 ± 5.0 µM) displayed comparable anti-HBV activity to NVR 3-778 (EC 50 = 0.73 ± 0.20 µM, CC 50 = 23.4 ± 7.0 µM). Besides, 7b showed improved water solubility (328.8 µg/mL, pH 7) compared to NVR 3-778 (35.8 µg/mL, pH 7). Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure–activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • DHA C-10 derivatives were designed, synthesized and evaluated by TLR4 antagonistic activities. • The electron-rich functional group is important for the DHA derivative's TLR4 antagonistic activity. • 2k with alkynyl as the end functional group exhibit 14 times more potent TLR4 antagonistic activity. • 2k inhibited LPS-induced TLR4 dimerization, endocytosis and NF-κB but not MAPKs activation. • DHA derivative 2k increased and prolonged morphine analgesia. Dihydroartemisinin (DHA), a natural product isolated from the traditional Chinese herb Artemisia annua and one of the clinical frontline drugs against malarial infections, has recently been discovered as a Toll-like Receptor 4 (TLR4) antagonist. However, the TLR4 antagonistic activity of DHA is modest and it exhibits cellular toxicity. In this work, the structure-activity relationship (SAR) of DHA as TLR4 antagonist was explored. Since destroying the sesquiterpene endoperoxide scaffold substantially compromised the TLR4 antagonistic activity and molecular dynamics analysis showed that the C-10 hydroxyl group formed a hydrogen bond with E72 of myeloid differentiation factor 2 (MD2) to prevent it moving deeper into MD2, SAR of DHA was focused on the C-10 hemiacetal position. With extending the length of the linear alkane chain at C10 position, the TLR4 antagonistic activity of DHA analogs increased first and then decreased with the best TLR4 antagonism occurring at the length of the carbon chain of 3–4 carbons. In contrast, the cellular toxicity of DHA analogs was raised with the increasing length of the linear alkane chain. The TLR4 antagonistic activity of DHA derivatives with substituted halogen as the terminal functional group decreased with the decrease of electronegativity of the substituted halogen, which implies the electron-rich functional group at the end of the alkane chain appears preferred. Therefore, DHA derivative 2k with alkynyl as the end functional group, exhibited 14 times more potent TLR4 antagonistic activity than DHA. Moreover, 2k showed less cellular toxicity than DHA. Cellular signaling characterizations indicated that 2k inhibited LPS-induced TLR4 dimerization and endocytosis and suppressed LPS-induced NF-κB but not MAPKs activation, culminating in blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO and IL-1β. Further, 2k was active in vivo ; it significantly increased and prolonged morphine analgesia. Collectively, this study provides a structural guidance to reposition DHA derivatives as TLR4 antagonists. [ABSTRACT FROM AUTHOR]

• Dynamic spreading of nanodroplets on nanostructured surfaces in electric fields is studied. • Effects of field strength, field direction, and intrinsic wettability are focused. • The pinning effect influences the electro-wettability and electro-stretching effects. • The contact angle in the upward electric field is larger than that in the downward electric field. Molecular dynamics simulations are implemented to investigate the statics and dynamics of wetting for a water nanodroplet on a nanostructured surface in the presence of a vertical electric field. The results show that the electric field induces electro-stretching, electro-wettability, modified solid-liquid interfacial tension, and pinning at the triple line, and they jointly affect the spreading exponent and static contact angle of the nanodroplet. Under an upward electric field, the spreading is always hindered, and the static contact angle monotonously increases with the field strength. Interestingly, under a downward electric field, the spreading is first hindered and then is promoted as increasing the field strength, leading to a first increased and then decreased static contact angle. The increased solid-liquid interfacial tension and the enhanced pinning are found to be two main mechanisms for the slowing down of spreading and the increase in static contact angles for both electric fields at low field strengths. The same trends are observed at high field strengths under the upward electric field; however, exactly the reverse trends occur under the downward electric field, leading to the acceleration of spreading and the decrease in static contact angle at high field strengths. Moreover, it is found that the enhancement in intrinsic wettability of the surface can suppress the breaking of hydrogen bonds, thereby reducing the solid-liquid interfacial tension and accelerating the spreading. The enhancement in intrinsic wettability can also reduce the pinning at the triple line as well as the energy barrier of the Cassie-Wenzel transition, which contributes to the reduced static contact angle. [ABSTRACT FROM AUTHOR]

Owing to scale effects, spreading of nanodroplets over heated textured surfaces displays distinct features from that of millimetric-sized droplets. In this work, spreading behaviors of a water nanodroplet on isothermally heated smooth and nanostructured surfaces are investigated for various surface temperatures, wettability, roughness via molecular dynamics (MD) simulations. The simulations show that, in the early spreading stage, the spreading radius of the nanodroplet on the textured surface is smaller than that on the smooth surface, whereas a reverse result was reported for millimetric-sized droplets. Because the nanodroplet size is comparable to the feature size of nanostructures, the pinning effect becomes prominent, leading to a large local dissipation in the vicinity of the contact line and hence hindering the nanodroplet spreading over the nanostructured surface. However, more drastic evaporation on the nanostructured surface in the later spreading stage facilitates the adsorption and desorption of water molecules, weakening the pinning effect. As a result, the difference in the spreading radius over the two surfaces becomes less obvious in the later spreading stage. The simulations also demonstrate that a higher surface temperature increases the spreading coefficient and promotes the evaporation, thereby accelerating the nanodroplet spreading; the nanodroplet spreading is significantly suppressed when the intrinsic wettability of the nanostructured surface changes from hydrophilic to moderate wettability; because of stronger pinning effect, the nanostructured surface with a larger aspect ratio exhibits a slower spreading. Moreover, owing to the influence of disjoining pressure, an abnormal evaporation phenomenon is observed for the intrinsically moderate wettability surface, on which the nanodroplet shows a much faster evaporation rate in the later spreading stage than that on intrinsically hydrophilic surfaces. • Spreading of nanodroplets on isothermally heated textured surfaces is studied. • Effects of surface temperature, intrinsic wettability, and roughness are focused. • Spreading on textured surfaces is slower than on smooth ones due to pining effect. • Evaporation weakens the pinning effect and hence promotes the spreading. • An abnormal evaporation phenomenon is observed in the later spreading stage. [ABSTRACT FROM AUTHOR]

Electrocoalescence has been extensively used to remove water droplets in water-in-oil emulsions. Pulsed direct current (DC) electric fields were found to be more effective than DC electric fields. However, as an essential process in electro-dehydration, coalescence dynamics of two charged droplets and corresponding coalescence mechanisms under pulsed DC electric fields have remained poorly understood. In this work, such coalescence dynamics behaviors are investigated via molecular dynamics simulations. The contact time of droplets, deformation ratio of coalescing droplets, and critical field strength are compared among square, sinusoidal, and triangular waves. The results show that, with the same pulse amplitude, the contact time is the shortest for the square wave, the following are sinusoidal and triangular waves. Sinusoidal and triangular waves have similar waveforms and they significantly differ from the square wave. However, it is astonishing that the contact times are very close for the square and sinusoidal waves, which are far less than that for the triangular wave. This seemingly abnormal result is reasonably explained by the equivalent field strength or RMS (root mean square) field strength. The square and sinusoidal waves have the same RMS field strength, whereas the triangular wave has a smaller RMS field strength. After two droplets coalesce into a large droplet, the coalescing droplet undergoes periodic deformation. The deformation ratio significantly depends on waveforms. As compared with sinusoidal and triangular waves, the deformation is much drastic for the square wave. The critical field strengths are also evaluated for the three waveforms. The result shows that the square and sinusoidal waves have almost the same critical field strength, whereas the triangular wave has a much higher critical field strength. Further analysis demonstrates that the RMS critical electric fields are actually the same for the three waveforms. • Electro-coalescence behaviors under pulsed direct electric fields are studied. • Three typical waveforms square, sinusoidal, and triangular waves are chosen. • Coalescence dynamics are compared for various waveforms. • Contact time, deformation ratio, and critical filed strength are evaluated. • The RMS electric field is used to explain the difference of coalescence dynamics. [ABSTRACT FROM AUTHOR]

• High-temperature spreading of Al-Cu(l)/Ni(s) and Al-Ni(l)/Ni(s) was studied. • Significant dissolution reaction occurs between drops and solid substrate. • Precursor film formation is suppressed by the dissolution reaction. • Dissolution of solid atoms into the droplet correspond to spreading enhancement. • Spreading rate is controlled by the lattice constants. The high-temperature spreading dynamics of Al-Cu(l)/Ni(s) and Al-Ni(l)/Ni(s) wetting systems was studied using molecular dynamics simulations. Accompanied with spreading, a significant dissolution reaction was noted to take place for the two studied systems. The dissolution reaction involves both diffusion of solid atoms into the droplet and incorporation of liquid atoms into the substrate. No precursor film is generated during spreading, since its formation is suppressed by the dissolution reaction. The dissolution reaction induces an enhanced spreading rate, and spreading becomes faster when droplets contain less Cu or Ni atoms. The dissolution of solid atoms into the droplet is faster than that of liquid atoms into the substrate, so that the dissolution of the former is the dominant driving force for the spreading enhancement. The spreading of Al-Cu droplets correlates with that of Al-Ni droplets so long as the Cu concentration in Al-Cu droplets is equal to the Ni concentration in Al-Ni droplets, since both Cu and Ni atoms have the identical lattice constants. [ABSTRACT FROM AUTHOR]

• Thermal rectification rate of the inclined nanojunction is higher than straight one. • Inclined nanojunction weakens local resonance compared to straight one. • Overlong inclined nanojunction can weaken the local resonance. • Thermal rectification is analyzed by dispersion mismatch and spectral heat flux. Introducing variable cross-section structures to graphene is considered to be an important method for producing thermal rectification (TR). In our work, non-equilibrium molecular dynamics simulations of variable cross-section graphene with nanojunctions were conducted, and their effects on thermal-transport properties were systematically studied. The results show that the introduction of nanojunctions can induce local phonon resonance effects, and the type of nanojunctions can influence these effects. The use of inclined nanojunctions can weaken local resonance compared to the use of straight nanojunctions. According to the results, the local resonance can be improved by increasing the length of the inclined nanojunctions within a certain range. However, beyond a specific length, the local resonance weakens. Finally, the directional difference in the phonon spectral heat flux and the directional mismatch of the dispersion curves are used to explain the TR phenomenon in the model. It is also found that low-frequency phonons play a key role in the TR phenomenon through the phonon density of states. This work provides guidance for designing local phonon resonance-based thermal rectifiers by tailoring graphene devices. [ABSTRACT FROM AUTHOR]

• Electrowetting transition on pillar-arrayed surfaces is studied. • MD simulations provide accurate wetting pathway. • Energy-minimization method is used to calculate the energy pathway. • Multiple energy barriers are found for the wetting transition. • Spontaneous dewetting transition occurs for a globally stable Cassie droplet. Two extreme wetting states, a highly non-wetting Cassie state and a wetting Wenzel state, can coexist or even mutually convert on patterned surfaces. Such a conversion process may be spontaneous or induced by external stimuli. This work studies the wetting transition of a nanodroplet on pillar-arrayed surfaces induced by an external electric field via an energy-minimization method in conjunction with molecular dynamics (MD) simulations. The simulation results reveal that driven by the electric field, the initial Cassie state could go through a partial wetting state, and eventually converts to the Wenzel state. The free-energy landscape reveals that there are multiple local energy minima, corresponding to multiple metastable states. For the metastable Cassie state, the wetting transition is irreversible, i.e., the droplet would remain in the Wenzel state when the electric field is removed. Conversely, the spontaneous dewetting transition from the Wenzel to the Cassie state can occur, if only the Cassie droplet is in a global energy minimum configuration. Thus, the stable Cassie wetting configuration is essential for triggering the spontaneous dewetting transition. [ABSTRACT FROM AUTHOR]

This work mainly focuses on the passive manipulation of the impact dynamics of nanodroplets using superhydrophobic surfaces decorated with a stepped surface via molecular dynamics (MD) simulations. Based on various impact conditions, we observe a series of novel impact dynamics that are quite different from the normal impact on smooth surfaces, mainly including the deflected rebound at the top/base of the stepped surface, and directional transport and splitting of droplets. The reason why the stepped texture can produce these fascinating dynamic characteristics is detailly investigated by calculating the centroid coordinate, free energy, and spread factor variations. The asymmetric dynamics of impacting droplets on stepped surfaces should be the primary reason for observed phenomena. The phase diagram is established to obtain overall insights into the impacting dynamics. This work can pave the way to assist practical applications, which require manipulating droplets at the nanoscale. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract The solubility of Vortioxetine hydrobromide (VORH) in three binary solvent mixtures of butanone + ethanol, butanone + n -propanol, and butanone + n -butanol was determined by the gravimetric method at temperatures ranging from (283.15 to 318.15) K. Surprisingly, the solubility displays a maximum at around 0.3 mol fraction of butanone in all three binary mixed solvents and this solvent composition was found to be independent of temperature. The solubility data was correlated by the modified Apelblat equation, λh equation, modified Jouyban-Acree model and NRTL model, and the modified Apelblat equation achieves the best fitting performance. Additionally, thermodynamic functions of mixing were derived, and the results suggest a spontaneous and entropy-driven mixing process. Molecular dynamic (MD) simulation was further employed to investigate solute-solvent and solvent-solvent interactions. Radial distribution function (RDF) analyses reveal that the rank of solute-solvent interactions correlates well with solubility order in binary solvent mixtures. The calculations of solvation free energy further confirm this correlation and the strongest interaction energy obtains at cosolvency composition in binary mixed solvents. Moreover, RDFs of solute-free binary solvent mixtures show that the composition of alcohols could alter the solvent (alcohol)-solvent (butanone) interactions and thereof influence interactions between VORH and butanone molecules in ternary system. The results thus indicate solvent-solvent interactions also play an important role in determining the solubility behavior. Therefore, both solute-solvent and solvent-solvent interactions were concluded to contribute to solubility behavior of VORH in three studied binary solvent mixtures. Graphical abstract RDF plots in the absence and presence of vortioxetine hydrobromide in butanone + n -butanol binary solvent mixtures at different solvent compositions of n -butanol. The data suggests both solute-solvent and solvent-solvent interactions contribute to the solubility behavior (cosolvency formation) of vortioxetine hydrobromide in binary mixed solvents. Unlabelled Image Highlights • Solubility of vortioxetine hydrobromide was measured by static method in three binary solvent mixtures • Thermodynamic analyses were performed based on functions of mixing • Solute-solvent and solvent-solvent interactions were probed by RDF and solvation free energy • The cosolvency solubility behavior was determined by both solute-solvent and solvent-solvent interactions [ABSTRACT FROM AUTHOR]

The high-temperature wetting of metal droplets on alloy metal substrates is of practical interest owing to its wide range of applications in brazing, welding and soldering. The surface and bulk of the alloy metals contain very many grain boundaries, whose effects on high-temperature wetting and the associated mechanisms have not been satisfactorily studied. In this work, two spreading scenarios are considered using molecular dynamics simulations to investigate the effects of grain boundaries on the wetting kinetics of the spreading of Al droplets on substrates with (polycrystalline NiAl) or without (monocrystalline NiAl) dissolutive reactions and at various rates of solution (monocrystalline and polycrystalline Ni 3 Al). Dissolutive reactions occur only when an Al droplet spreads over a polycrystalline NiAl substrate, and they significantly accelerate the wetting kinetics. Irregular atomic alignment and associated with grain boundaries, atomic migration or dissolution reactions occur more easily on grain boundaries than on ideal crystal substrates. Dissolutive reactions occur when Al droplets spread on either monocrystalline or polycrystalline Ni 3 Al substrates; however, grain boundaries influence the dissolution rates in various spreading stages. The dissolution rate of the Al(l)/polycrystalline Ni 3 Al(s) system with grain boundaries exceeds that of the Al(l)/monocrystalline Ni 3 Al(s) system in the initial stage of spreading, but is less than that of the Al(l)/monocrystalline Ni 3 Al(s) system in the final stage of spreading. Correspondingly, the spreading of the Al(l)/polycrystalline NiAl(s) system is faster than that of Al(l)/monocrystalline NiAl(s) system in the first stage but slower in the last stage. This result confirms that dissolutive wetting is dominated by dissolutive rate rather than by the total dissolutive quantity, and a high dissolution rate accelerates wetting. [ABSTRACT FROM AUTHOR]

In this work, the influence of a monolayer graphene (MLG) on the wetting behaviors of grooved copper is thoroughly investigated. Our outcomes signify that the coating with MLG can remarkably reduce the activation energy required for the infiltration of the water molecules film into copper grooves, thereby triggering the wetting transition from the Cassie-Baxter (CB) to Wenzel (WZ) state. The tunable wettability by the coating engineering approach of MLG is holding great potentials for the fabrication of high aspect ratio structures. [Display omitted] • The wettability of the grooved copper surface is thoroughly investigated. • The monolayer graphene coating triggered wetting (CB-to-WZ) transitions on the structured surface. • The sidewall graphene plays an important role in activating the penetration of the water molecular into the groove. • MLG-coating provides a new route for the fabrication of high aspect ratio micro/nano structures. The various high aspect ratio micro/nano structures that are duplicated by the widely applicable micro/nanomolding process would require excellent wettability of the structured mold for full filling of the liquid-like materials into microcavities. Herein, by employing molecular dynamics (MD) simulations, the influence of a monolayer graphene (MLG) on the wetting behaviors of grooved copper is thoroughly investigated, indicating that MLG is an effective approach in modulating the wettability of the structured copper surfaces. Moreover, the extracted outcomes signify that the coating with MLG reduces remarkably the required activation energy for the infiltration of water molecules into the copper groove, thereby triggering the wetting transition from the Cassie-Baxter (CB) to the Wenzel (WZ) state. In addition, by varying the coating locations and dimension of the MLG, it is unveiled that the sidewall coating of MLG plays a crucial role in reducing the free energy barrier needed to surmount the transition state. Interestingly, as the coating height of sidewall MLG increases, the energy barrier is reduced, and the grooved surface becomes more attractive to water molecular, attaining a stable WZ state by employing a height beyond the critical value of MLG coating of 12.4 Å in our model. Our work provides useful insights into the tunable wettability of the grooved surfaces by nanocoating engineering, suggesting that MLG can be an effective coating solution in the fabrication of novel micro/nanostructures with high aspect ratios. [ABSTRACT FROM AUTHOR]

The distribution of hydrogen bond density along z -axis at different salt concentrations and the images inside the graph show the criteria of hydrogen bonds. • The wetting mechanism of NaCl solution on the surface of MgO is investigated. • Ion hydration breaks the hydrogen bond network in the hydration layer and bulk. • The orientation of water molecules can be changed by ion hydration. • Ion hydration leads to the ordered structure of first hydration layer. • The contact angle increases almost linearly with the salt concentration. The effects of NaCl solution concentrations on the water wettability of the MgO surface have been studied using molecular dynamics simulations. We find that ion hydration has a strong ability to dominate the structure of water network in the hydration layer. It can transform the orientation of water OH bonds, and reconstruct an ordered water network in the first layer, which in turn reduces the density of inter-layer hydrogen bonds. This further results in weak interactions between the first hydration layer and the actual droplet above the hydration layer, eventually increasing the hydrophobicity of the MgO(001) surface and corrosion resistance. [ABSTRACT FROM AUTHOR]