Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder-Decoder Model.

The receptor tyrosine kinase RET (rearranged during transfection) plays a vital role in various cell signaling pathways and is a critical factor in the development of the nervous system. Abnormal activation of the RET kinase can lead to several cancers, including thyroid cancer and non-small-cell lung cancer. However, most RET kinase inhibitors are multi-kinase inhibitors. Therefore, the development of an effective RET-specific inhibitor continues to present a significant challenge. To address this issue, we built a molecular generation model based on fragment-based drug design (FBDD) and a long short-term memory (LSTM) encoder-decoder structure to generate receptor-specific molecules with novel scaffolds. Remarkably, our model was trained with a molecular assembly accuracy of 98.4%. Leveraging the pre-trained model, we rapidly generated a RET-specific-candidate active-molecule library by transfer learning. Virtual screening based on our molecular generation model was performed, combined with molecular dynamics simulation and binding energy calculation, to discover specific RET inhibitors, and five novel molecules were selected. Further analyses indicated that two of these molecules have good binding affinities and synthesizability, exhibiting high selectivity. Overall, this investigation demonstrates the capacity of our model to generate novel receptor-specific molecules and provides a rapid method to discover potential drugs.

Discovery of potential RIPK1 inhibitors by machine learning and molecular dynamics simulations.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in inflammation and cell death, so it is a promising candidate for the treatment of autoimmune, inflammatory, neurodegenerative, and ischemic diseases. So far, there are no approved RIPK1 inhibitors available. In this study, four machine learning algorithms were employed (random forest, extra trees, extreme gradient boosting and light gradient boosting machine) to predict small molecule inhibitors of RIPK1. The statistical metrics revealed similar performance and demonstrated outstanding predictive capabilities in all four models. Molecular docking and clustering analysis were employed to confirm six compounds that are structurally distinct from existing RIPK1 inhibitors. Subsequent molecular dynamics simulations were performed to evaluate the binding ability of these compounds. Utilizing the Shapley additive explanation (SHAP) method, the 1855 bit has been identified as the most significant molecular fingerprint fragment. The findings propose that these six small molecules exhibit promising potential for targeting RIPK1 in associated diseases. Notably, the identification of Cpd-1 small molecule (ZINC000085897746) from the Musa acuminate highlights its natural product origin, warranting further attention and investigation.

A Workflow Combining Machine Learning with Molecular Simulations Uncovers Potential Dual-Target Inhibitors against BTK and JAK3.

The drug development process suffers from low success rates and requires expensive and time-consuming procedures. The traditional one drug-one target paradigm is often inadequate to treat multifactorial diseases. Multitarget drugs may potentially address problems such as adverse reactions to drugs. With the aim to discover a multitarget potential inhibitor for B-cell lymphoma treatment, herein, we developed a general pipeline combining machine learning, the interpretable model SHapley Additive exPlanation (SHAP), and molecular dynamics simulations to predict active compounds and fragments. Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are popular synergistic targets for B-cell lymphoma. We used this pipeline approach to identify prospective potential dual inhibitors from a natural product database and screened three candidate inhibitors with acceptable drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Ultimately, the compound CNP0266747 with specialized binding conformations that exhibited potential binding free energy against BTK and JAK3 was selected as the optimum choice. Furthermore, we also identified key residues and fingerprint features of this dual-target inhibitor of BTK and JAK3.

Realizing Efficient Catalytic Performance and High Selectivity for Oxygen Reduction Reaction on a 2D Ni2SbTe2 Monolayer.

One of the immediate challenges for the large-scale commercialization of hydrogen-based fuel cells is to develop cost-effective electrocatalysts to enable cathodic oxygen reduction reaction (ORR). Herein, we focus on the potential of the two-dimensional (2D) ternary chalcogenide Ni2SbTe2 monolayer as a high-performance electrocatalyst for the ORR using density function theory. Our computed results reveal that there are an obvious hybridization and electron transfer between the O 2p and Te 5p orbitals, which can activate the adsorbed oxygen and trigger the whole ORR process, with an overpotential as low as 0.33 V. In addition, the adsorption capacity of the monolayer surface for oxygen molecules can be effectively enhanced by doping with Fe or Co atoms. The Ni2SbTe2 monolayers doped with Fe or Co atoms not only maintain their original excellent ORR catalytic activity but also improve selectivity toward the four-electron (4e) reduction pathway. We highly anticipate that this work can provide excellent candidates and new ideas for designing low-cost and high-performance ORR catalysts to replace noble metal Pt-based catalysts in fuel cells.

Generation of singlet oxygen catalyzed by the room-temperature-stable anthraquinone anion radical.

The chemical nature and the catalytic selectivity of the complex of anthraquinone and potassium tert-butoxide, AQ-KOtBu, in generating singlet oxygen (1O2) have been studied using a high-level ab initio method and density functional theory (DFT). The results suggest that the stable catalytic center of the AQ anion radical (semiquinone, [AQ˙]-) can be produced at room temperature, which is due to the strong delocalization characteristics of electrons in potassium atoms. Two experimentally observed complexes, the ground state AQ-KOtBu, i.e., C(1), and the photoexcited AQ-KOtBu, i.e., C(2), can be distinguished via the two different electronic states (π-type and σ-type) of the tert-butoxide group. More interestingly, the catalytic selectivity of AQ-KOtBu to generate 1O2 was investigated using multistate density functional theory (MSDFT), and the results suggest that only open-shell 1O2 rather than the closed-shell component can be generated. This work explores the electronic structure and the catalytic nature of AQ-KOtBu, which is of great importance for the application of AQ and its derivatives.

Theoretical Study on a Potential Oxygen Reduction Reaction Electrocatalyst: Single Fe Atoms Supported on Graphite Carbonitride.

In recent years, one of the research directions of proton-exchange membrane fuel cells (PEMFCs) was to exploit efficient electrocatalysts for oxygen reduction reaction (ORR) instead of precious metals. In this study, on the basis of the density-functional theory (DFT) calculations, we designed a new type of single-atom ORR electrocatalyst by doping single iron atoms into the N-coordination cavity of the substrate graphite carbonitride (Fe/g-C3N4). The adsorption site and the adsorption energy of all the intermediates, the reaction energy barriers, potential energy surface, and Mulliken charges have been analyzed. The feasible ORR reaction paths and the most favorable ORR reaction mechanism were performed. Our calculation results prove that Fe/g-C3N4 is a potential electrocatalyst toward ORR. This work proposes a novel notion for the development of cathode materials in PEMFCs.

Mechanistic Insight into Pd(II)-Catalyzed Late-Stage Nondirected C(sp2)-H Cyanation of Toluene Using the Dual Ligands MPAA and Quinoxaline: A Density Functional Theory Investigation.

Density functional theory (DFT) calculations were performed to investigate the mechanism of Pd(II)-catalyzed late-stage nondirected C(sp2)-H cyanation of toluene. We confirmed the resting state and catalytic active species of this stoichiometric reaction, and we calculated the full catalytic cycle to obtain a favorable reaction pathway. The DFT calculation results indicate that the morphology of the active species is essential for the observed concerted metalation/deprotonation step. Although C-H activation is reversible in principle, it is the regioselectivity- or product-determining step. Our calculation results show that the regioselectivity is not only influenced by the electron effects but also by the potential steric repulsion interactions between the substrates and the specific geometry of the catalyst. Interestingly, the transmetalation process involves the largest overall change in free energy; thus, transmetalation is defined as the rate-determining step and turnover-determining step.

Embedding tetrahedral 3d transition metal TM4 clusters into the cavity of two-dimensional graphdiyne to construct highly efficient and nonprecious electrocatalysts for hydrogen evolution reaction.

On the basis of density functional theory (DFT) calculations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for a series of new composite systems TM4@GDY (TM = Sc, Ti, Mn, Fe, Co, Ni and Cu), which are constructed by embedding tetrahedral 3d transition metal TM4 clusters in the in-plane cavity of two-dimensional (2D) π-conjugated graphdiyne (GDY). Our computed results reveal that compared with the constituent subunits, namely the sole TM4 cluster and GDY, all these composite TM4@GDY nanostructures can uniformly exhibit considerably high HER catalytic activity over a wide range of hydrogen coverage, and especially the Fe4@GDY and Co4@GDY systems can possess higher HER activity, in view of their higher number of active sites. The high HER catalytic activity for TM4@GDY can be mainly due to the occurrence of obvious electron transfer from TM4 cluster to GDY, significantly activating the correlative C and TM atoms. Moreover, all these composite TM4@GDY systems can also exhibit high structural stability and good conductivity. Therefore, all of them can be considered as a new kind of promising HER catalyst, and this study can provide new strategies for designing low-cost and high-performance 2D carbon-based electrocatalysts.

Theoretical predication of the high hydrogen evolution catalytic activity for the cubic and tetragonal SnP systems.

By means of density functional theory (DFT) calculations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for the cubic and tetragonal SnP systems, both of which can be viewed as the stacking of SnP layers possessing structural features similar to the famous phosphorene. It is revealed that the (111) and (200) facets are the possible exposed surfaces of the cubic structure, while the possible exposed surfaces of the tetragonal structure are (101), (101[combining macron]), (110), (002) and (002[combining macron]) facets. The computed surface energies reveal that the P-terminated (111) surface and the (200) surface of the cubic SnP system as well as the P-terminated (101) and (101[combining macron]) surfaces and the (110) surface of the tetragonal SnP system can be considered as the more stable surfaces, in view of more favorable surface energy. The computed free energy values of H* (ΔGH*) show that all these stable surfaces can possess considerably high HER catalytic activity over a wide range of hydrogen coverage. It is found that the top sites over P atoms can serve as the most active sites on these surfaces, and the tetragonal structure can even exhibit a higher HER activity than the cubic structure. Moreover, the correlative catalytic mechanisms have been analyzed in detail. Coupled with the metallic conductivity, two kinds of bulk SnP systems can be very promising candidates as a high-performance and low-cost HER electrocatalyst. All these fascinating findings can be beneficial for promoting the application of excellent SnP-based materials in catalyzing the water splitting process.

Theoretical design of a series of 2D TM-C3N4 and TM-C3N4@graphene (TM = V, Nb and Ta) nanostructures with highly efficient catalytic activity for the hydrogen evolution reaction.

Inspired by the fascinating result that NbN-related species can possess a similar electronic structure to noble metal atoms (e.g. Pt), in this work we have proposed for the first time a new strategy, through embedding the transition metal (TM) Nb atom in the in-plane cavity of g-C3N4, for constructing the nonprecious Nb-C3N4 configuration comprising the NbN unit exhibiting noble-metal-like characteristics. Our computed results reveal that embedding Nb can significantly improve the catalytic activity for the hydrogen evolution reaction (HER) of g-C3N4, and even that the formed Nb-C3N4 can exhibit a considerably high HER catalytic activity over a wide range of hydrogen coverage. Similarly, such a high HER activity can also be observed in the analogous V- or Ta-doped g-C3N4 systems. Furthermore, a series of new hybrid systems TM-C3N4@G (TM = V, Nb or Ta) is constructed by coupling the single-layered TM-C3N4 with graphene, and all of them can also possess a considerably high HER catalytic activity over a wide range of hydrogen coverage. Moreover, all these composite TM-C3N4 and TM-C3N4@G systems possess high structural stability and metallic conductivity. Thus, all of them can be viewed as a new class of promising HER catalysts, and this work can also provide new strategies for designing low-cost and high-performance electrocatalysts.

Highly efficient catalytic activity for the hydrogen evolution reaction on pristine and monovacancy defected WP systems: a first-principles investigation.

Using density functional theory (DFT) calculations, we have comprehensively investigated the structure and the hydrogen evolution reaction (HER) catalytic activity for pristine and monovacancy defected WP systems. It was revealed that the (101) surface can have the most exposure for the WP structure. The calculated free energy values of H* (ΔGH*) show that the (101) surface can exhibit good HER catalytic activity, where the top site over the W atoms can act as the most active site for HER due the existence of antibonding characteristics after adsorbing H*. Moreover, we have proposed an effective strategy through the introduction of a monovacancy to further improve the HER activity of the WP system. It was found that the formation of the W-monovacancy can significantly improve HER activity since the decreased coordination number of the correlative atoms brings some new active sites around the defect. Particularly, these systems can even exhibit considerably high HER activity over a wide range of hydrogen coverage. Clearly, all these fascinating findings at the atomic level can be beneficial for realizing highly efficient nonprecious HER electrocatalysts based on tungsten phosphide and even other transition metal phosphides in the near future.

Theoretical insights into the effective hydrogen evolution on Cu3P and its evident improvement by surface-doped Ni atoms.

On the basis of the first-principles DFT computations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for pristine and Ni-doped Cu3P systems. It was revealed that the (11[combining macron]0) surface could be the one with the most exposure for the Cu3P structure. The calculated free energy values of H* (ΔGH*) are in the range from 0.012 to 0.320 eV, reflecting the HER activity on the (11[combining macron]0) surface, which is consistent with the experimentally reported results. Our computed results also reveal that the top sites over P atoms as well as the bridge and hollow sites composed of Cu atoms can make the main contribution to the HER activity on the (11[combining macron]0) surface, and the hollow sites (ΔGH* ≈ 0 eV) can serve as the most active sites due to the considerably flexible structural features. Furthermore, we have proposed an effective strategy through doping Ni to significantly improve the HER catalytic activity on the (11[combining macron]0) surface by effectively optimizing the adsorption state of H* based on the case that Ni and Cu have the opposite ability to bind with H. All these doped systems can uniformly possess high HER activity, and particularly some doped structures with the appropriate Ni-atom number can even exhibit considerably high HER activity over a wide range of H coverage, indicating the more excellent catalytic performance. It is worth mentioning that the surface-metal-atoms for these Ni-doped systems can still exhibit flexible behavior, which can also be beneficial for realizing high HER activity. These fascinating theoretical insights at the atomic level can be advantageous for achieving highly efficient non-precious HER electrocatalysts based on copper phosphide and even other transition metal phosphides in the near future.

A theoretical study on the structures and electronic and magnetic properties of new boron nitride composite nanosystems by depositing superhalogen Al13 on the surface of nanosheets/nanoribbons.

Inorganic boron nitride (BN) nanomaterials possess outstanding physical and chemical characteristics, and can be considered as an excellent building block to construct new composite nanomaterials. In this work, on the basis of the first-principles computations, a new type of composite nanostructure can be constructed by depositing superhalogen Al13 on the surface of low-dimensional BN monolayer or nanoribbons (BNML/BNNRs). All these Al13-modified BN nanosystems can possess large adsorption energies, indicating that superhalogen Al13 can be stably adsorbed on the surface of these BN materials. In particular, it is revealed that independent of the chirality, ribbon width and adsorption site, introducing superhalogen Al13 can endow the BN-based composite systems with a magnetic ground state with a magnetic moment of about 1.00 µB, and effectively narrow their robust wide band gaps. These new superhalogen-Al13@BN composite nanostructures, with magnetism and an appropriate band gap, can be very promising to be applied in multifunctional nanodevices in the near future.

Reaction of CO2 with Atomic Transition Metal M+/0/- Ions: A Theoretical Study.

The activation of carbon dioxide mediated by the first row 3d transition metal (TM) M+/0/- atomic ions was studied theoretically. Theoretical calculations show left-hand transition-metal ions Sc+, Sc, Ti+, Ti, and V can mediate oxygen atom transfer (OAT) from carbon dioxide. In the anionic system, for early transition metal ions (Sc to Cr), [OM-CO]- are more stable than [M-OCO]-, while the others favor binding formation, [M-OCO]-. TSR was observed in O atom transfer. The OAT reaction is exothermic only for the first three transition metal cations and atoms (Sc+/0, Ti+/0, and V+/0), Fe0 and all the anions except Cu- and Zn-. Furthermore, in most case, reaction enthalpy, and energy barrier of OAT for the cationic system is the highest, and the anionic system is the lowest. We discuss the performances of 18 methods on the energies and structures.

Highly Active, Nonprecious Electrocatalyst Comprising Borophene Subunits for the Hydrogen Evolution Reaction.

Developing nonprecious hydrogen evolution electrocatalysts that can work well at large current densities (e.g., at 1000 mA/cm2: a value that is relevant for practical, large-scale applications) is of great importance for realizing a viable water-splitting technology. Herein we present a combined theoretical and experimental study that leads to the identification of α-phase molybdenum diboride (α-MoB2) comprising borophene subunits as a noble metal-free, superefficient electrocatalyst for the hydrogen evolution reaction (HER). Our theoretical finding indicates, unlike the surfaces of Pt- and MoS2-based catalysts, those of α-MoB2 can maintain high catalytic activity for HER even at very high hydrogen coverage and attain a high density of efficient catalytic active sites. Experiments confirm α-MoB2 can deliver large current densities in the order of 1000 mA/cm2, and also has excellent catalytic stability during HER. The theoretical and experimental results show α-MoB2's catalytic activity, especially at large current densities, is due to its high conductivity, large density of efficient catalytic active sites and good mass transport property.

Layer-independent and layer-dependent nonlinear optical properties of two-dimensional GaX (X = S, Se, Te) nanosheets.

Recently researchers have found that the non-resonant second-harmonic generation (SHG) intensity of the GaSe monolayer (ML) is the strongest among all two-dimensional (2D) atomic layered crystals. Here we perform a systematic first-principles study of the SHG coefficient of GaX (X = S, Se, Te) monolayers (MLs) and few-layers. We find that the non-resonant SHG intensity of the GaS ML can be comparable with that of the GaSe ML, while the non-resonant SHG intensity of the GaTe ML is much stronger than that of the GaSe ML. Furthermore, the magnitudes of SHG coefficients of the few-layers exfoliated from bulk ε-GaSe and newly constructed N1-GaSe crystals are very close to that of the GaSe ML, showing no dependence on the layer number. The magnitude of the SHG coefficient of the trilayer exfoliated from the bulk ß-GaSe crystals is around 1/3 of that of the GaSe ML, decreasing rapidly with the layer number. This study indicates that a strong SHG response can be obtained in a wide range of monolayers and few-layers. Moreover, we point out that one can identify the layer number and the stacking sequence of 2D nanosheets by measuring their elastic constants and SHG coefficients.

Introducing the triangular BN nanodot or its cooperation with the edge-modification via the electron-donating/withdrawing group to achieve the large first hyperpolarizability in a carbon nanotube system.

Based on the ab initio calculations, we first investigated the nonlinear optical (NLO) properties of the doped carbon nanotube (CNT) systems with a triangular BN nanodot with the central B or N atom. Our computed results reveal that introducing the triangular BN nanodot can be considered as a new strategy to effectively enhance the first hyperpolarizability ß0 value of a CNT system, and the type and size of the triangular BN domain have an important effect on the ß0 value of the hybrid CNT system. In addition, the n-type doping by introducing the triangular BN nanodot with more N atoms, viewed as injecting electrons into the CNT system, can more effectively increase the ß0 value of the hybrid CNT system when the doped domains have the same size. Moreover, the ß0 value of the hybrid CNT system can be further enhanced by employing the electron-donating or -withdrawing group (NH2/NO2) to modify the appropriate nanotube-edged site to build the typical donor-π-acceptor framework, in view of the occurrence of a more effective charge transfer process. Evidently, this type of cooperation of introducing the triangular BN nanodot and forming the donor-π-acceptor framework can be considered as another new strategy to significantly enhance the first hyperpolarizability of the CNT system. These appealing findings can provide valuable insights into the design of novel high-performance NLO materials based on carbon nanotubes.

Adsorbing the 3d-transition metal atoms to effectively modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons.

On the basis of first-principles computations, we propose a simple and effective strategy through surface-adsorbing 3d-transition metal (TM) atoms, including Ti, Cr, Mn, Fe and Co, to modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons (zSiCNRs), in view of the unique d electronic structures and intrinsic magnetic moments of TM atoms. It is revealed that like applying an electric field, the adsorption of these transition metal atoms can induce an evident change in the electrostatic potential of the substrate zSiCNRs owing to the electron transfer from the TM atom to the substrate. This can break the magnetic degeneracy of zSiCNRs and solely ferromagnetic (FM) or antiferromagnetic (AFM) metallicity and even intriguing FM or AFM half-metallicity can be observed in the TM-modified zSiCNR systems. Moreover, all these modified systems can exhibit considerably large adsorption energies ranging from -0.872 eV to -4.304 eV, indicating their considerably high structural stabilities. These intriguing findings will be advantageous for promoting excellent SiC-based nanomaterials in the practical application of spintronics and multifunctional nanodevices in the near future.

Second harmonic generation property of monolayer TMDCs and its potential application in producing terahertz radiation.

Second harmonic generation (SHG) properties in two-dimensional (2D) transition-metal dichalcogenides (TMDCs) have aroused great interest. However, until now SHG for TMDC monolayer alloys is seldom investigated. Meanwhile, there is considerable controversy over the static SHG coefficients of monolayer MoS2. The feasibility to produce terahertz (THz) radiation via SHG in pure and alloyed TMDCs has never been reported. We first calculate the SHG coefficients of monolayer MoS2, MoSe2, and MoS2(1-x)Se2x using the independent particle approximation plus scissors correction. We then simulate their THz absorption by applying density function perturbation theory plus the Lorentzian line and try to calculate their zero-frequency THz refractive index and birefringence. The physical property of MoS2(1-x)Se2x alloys is simulated by considering various combinations. Results indicate that monolayer MoS2, MoSe2, and MoS2(1-x)Se2x possess large static SHG coefficients and THz birefringence and display low absorption over broadband THz frequencies. Therefore, they have applications in producing THz radiation via SHG. This study demonstrates that THz radiation can be attained in a large number of monolayers and few-layers and will extend applications of 2D materials. Moreover, it is possible to identify the magnitude of static coefficients of single-layer MoS2 by measuring THz intensities.

Realizing diverse electronic and magnetic properties in hybrid zigzag BNC nanoribbons via hydrogenation.

By means of first-principles DFT computations, we systematically investigate the geometries, stabilities, electronic and magnetic properties of fully and partially hydrogenated zigzag BNC nanoribbons (fH-zBNCNRs and pH-zBNCNRs) with interfacial N-C or B-C connections. It is revealed that in the lowest-lying configuration of hybrid fH-zBNCNRs, the constituent C and BN segments can possess respective chair and boat conformations and both of them are connected by the chair mode, independent of the N-C/B-C interface. Changing the ribbon width and the ratio of BN to C can endow these fH-zBNCNR systems with abundant electronic and magnetic properties involving nonmagnetic (NM) semiconductivity, ferromagnetic (FM) metallicity, antiferromagnetic (AFM) metallicity as well as AFM half-metallicity. Besides, manipulating the hydrogenation pattern and ratio can also result in rich electronic and magnetic behaviors in pH-zBNCNRs, where NM semiconductivity, AFM semiconductivity, AFM metallicity and even AFM spin gapless semiconductor are observed. Additionally, the origin of the magnetism in these hydrogenated zBNCNRs is analyzed in detail. Finally, all of these hydrogenated BNC structures can possess a favorable formation energy, large binding energy per hydrogen atom and high thermal stability, indicating the great possibility of their experimental realization by hydrogenating pristine zBNCNRs. These valuable insights can be advantageous for promoting hybrid BNC-based nanomaterials in the applications of spintronics and multifunctional nanodevices.