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.

Inhibition mechanism understanding from molecular dynamics simulation of the interactions between several flavonoids and proton-dependent glucose transporter.

Proton-dependent glucose transporters as important drug targets can have different protonation states and adjust their conformational state under different pHs. So based on this character, research on its inhibition mechanism is a significant work. In this article, to study its inhibitory mechanism, we performed the molecular dynamics of several classical flavonoid molecules (Three inhibitors Phloretin, Naringenin, Resveratrol. Two non-inhibitors Isoliquiritigenin, Butein) with glucose transporters under two distinct environmental pHs. The results show inhibitors occupy glucose binding sites (GLN137, ILE255, ASN256) and have strong hydrophobic interactions with proteins through core moiety (C6-Cn-C6). In addition, inhibitors had better inhibitory effects in protonation state. In contrast, non-inhibitors can not occupy glucose binding sites (GLN137, ILE255, ASN256), thus they do not have intense interactions with the protein. It is suggested that favorable inhibitors should effectively take up the glucose-binding site (GLN137, ILE255, ASN256) and limit the protein conformational changes.Communicated by Ramaswamy H. Sarma.

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.

2D RhTe Monolayer: A highly efficient electrocatalyst for oxygen reduction reaction.

Oxygen reduction reaction (ORR) electrocatalysts with excellent activity and high selectivity toward the efficient four-electron (4e) pathway are very important for the wide application of fuel cells and are worth searching vigorously. In this study, r-RhTe monolayer is identified as a good ORR electrocatalyst from three 2D RhTe configurations with low Rh-loading (i.e., r-RhTe, o-RhTe and h-RhTe) on the basis of the first-principles calculations. For the most energetically stable r-RhTe, two adjacent positively charged Te atoms on the material surface can provide an active site for oxygen dissociation. Coupled with its high stability and intrinsic conductivity, 2D r-RhTe monolayer is confirmed to possess good catalytic activity and high reaction selectivity toward ORR. Moreover, under the ligand effect caused by the substitution of Cr, Mn and Fe, the ORR catalytic activity of r-RhTe monolayer could be effectively enhanced, where very small over-potential was achieved, and even comparable to or lower than the state-of-the-art Pt (111). This shows it has considerably high ORR activity. This work is highly anticipated to provide excellent candidate materials for ORR catalysis, and the related researches based on the Rh-Te materials will provide a new way to design high-performance ORR electrocatalysts to substitute the precious metal Pt-based catalysts.

Reaction of Ta3 - Clusters with Molecular Nitrogen: A Mechanism Investigation.

Because of the inertness of molecular nitrogen, its practicable activation under mild conditions is a fundamental challenge. Ta3 - is an exceptionally small cluster that reacts with N2 at room temperature, leading finally to Ta3N2 -; Ta3N2 - also could react with N2 at room temperature, leading finally to Ta3N4 -, a product of interest in its own right because of its potential as a nitrogen fixation medium. The mechanisms of the Ta3 -- and Ta3N2 --mediated activation of the N≡N triple bond have been investigated. Our extensive computations elucidate mechanisms for the ready reactions, leading to stepwise cleavage of the N≡N bond. Initial isomeric N2/Ta3 - complexes, N≡N elongation, undergo a N≡N split over generally low barriers in a highly exothermic process. The nitrogen-atom or molecular exchange reactions found in the Ta3N2 -/N2 system may be of paramount importance in both applied and fundamental studies.

Accurate Adiabatic and Diabatic Potential Energy Surfaces for the Reaction of He + H2.

The accurate adiabatic and diabatic potential energy surfaces, which are for the two lowest states of He + H2, are presented in this study. The Molpro 2012 software package is used, and the large basis sets (aug-cc-pV5Z) are selected. The high-level MCSCF/MRCI method is employed to calculate the adiabatic potential energy points of the title reaction system. The triatomic reaction system is described by Jacobi coordinates, and the adiabatic potential energy surfaces are fitted accurately using the B-spline method. The equilibrium structures and electronic energies for the H2 are provided, and the corresponding different levels of vibrational energies of the ground state are deduced. To better express the diabatic process of the whole reaction, avoid crossing points being calculated and conical intersection also being optimized. Meanwhile, the diabatic potential energy surfaces of the reaction process are constructed. This study will be helpful for the analysis of histopathology and for the study in biological and medical mechanisms.

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.

The Reaction Mechanism Study for the F3 System.

In order to study the F3 system, an accurate global adiabatic potential energy surface is reduced in the present work. The high-level ab initio (MCSCF/MRCI level) methods with big basis set aVQZ are used to calculate 27690 potential energy points in the MOLPRO quantum chemistry package using the Jacobi coordinate. Meanwhile, the B-spline fit method is used to reduce the global potential energy surface in this present work. The shallow well complexes are found in the present work when the angles θ = 30°, 60°, and 90°. Analysing the global potential energy surfaces can get the conclusion that reactants should overcome at least 0.894 eV energy to cross the transition state and reach products. This study will be helpful for the analysis in histopathology and for the study of biological and medical mechanisms.

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.

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.

Probing the activity of transition metal M and heteroatom N4 co-doped in vacancy fullerene (M-N4-C64, M = Fe, Co, and Ni) towards the oxygen reduction reaction by density functional theory.

In this study, a novel type oxygen reduction reaction (ORR) electrocatalyst is explored using density functional theory (DFT); the catalyst consists of transition metal M and heteroatom N4 co-doped in vacancy fullerene (M-N4-C64, M = Fe, Co, and Ni). Mulliken charge analysis shows that the metal center is the reaction site of ORR. PDOS analysis indicates that in M-N4-C64, the interaction between Fe-N4-C64 and the adsorbate is the strongest, followed by Co-N4-C64 and Ni-N4-C64. This is consistent with the calculated adsorption energies. By analyzing and comparing the adsorption energies of ORR intermediates and activation energies and reaction energies of all elemental reactions in M-N4-C64 (M = Fe, Co, and Ni), two favorable ORR electrocatalysts, Fe-N4-C64 and Co-N4-C64, are selected. Both exhibited conduction through the more efficient 4e- reduction pathway. Moreover, PES diagrams indicate that the whole reaction energy variation in the favorable ORR pathways of Fe-N4-C64 and Co-N4-C64 is degressive, which is conducive to positive-going reactions. This study offers worthwhile information for the improvement of cathode materials for fuel cells.

Investigation of binding modes of spider toxin-human voltage-gated sodium channel subtybe 1.7.

ABSTRACTSThe human voltage-gated sodium channel subtype 1.7 (hNaV1.7) is an attractive target for the development of potent and selective novel analgesics. HwTx-IV, a spider derived peptide toxin with 35-residue, inhibits hNaV1.7 with high potency by influencing the kinetics and gating behaviors of the channel, kinetics refers to the control of ion channels on and off by binding to a voltage sensor domains, so it is classified as gating modifier toxins (GMTs). In this study, we study how HwTx-IV and its variant exert its inhibitory potency on hNav1.7 using a range of biophysical techniques including homology modelling, molecular docking, molecular dynamics simulation, and umbrella sampling. The results show that the binding free energy of HwTx-IV and m3-HwTx-IV to hNaV1.7 is -15.00 kJ/mol and -16.2 kJ/mol, respectively, which are consistent with the experiential results；hydrophobic and electrostatic interaction both are important concerns about toxin blocking ion channels：the interactions of m3-HwTx-IV-hNaV1.7 are enhanced by mutating several residues in HwTx-IV. In comparison with the other peptide toxins of NaSpTx-F1, it is found that NaSpTx-F1 also had a similar binding characteristic. Combined above results, it was concluded that K32, W30 and F6, K7 and A8 in N-groove were critical for the interaction strength；G1, L3, G4, I5 in the N terminus and W33, I35 in the C terminus together can determine the peptide binding orientation relative to the channel and ultimately altered the inhibitory effect. This conclusion would be useful for designing high potency peptide inhibitor for hNav1.7.Communicated by Ramaswamy H. Sarma.

The binding process of BmKTX and BmKTX-D33H toward to Kv1.3 channel: a molecular dynamics simulation study.

The potassium channel Kv1.3 is an important pharmacological target and the Kaliotoxin-type toxins (α-KTX-3 family) are its specific blockers. Here, we study the binding process of two kinds of Kaliotoxin-type toxins:BmKTX and its mutant (BmKTX-D33H) toward to Kv1.3 channel using MD simulation and umbrella sampling simulation, respectively. The calculated binding free energies are -27 kcal/mol and -34 kcal/mol for BmKTX and BmKTX-D33H, respectively, which are consistent with experimental results. The further analysis indicate that the characteristic of electrostatic potential of the α-KTX-3 have important effect on their binding modes with Kv1.3 channel; the residue 33 in BmKTX or BmKTX-D33H plays a key role in determine their binding orientations toward to Kv1.3 channel; when residue 33 (or 34) has negative electrostatic potential, the anti-parallel ß-sheet domain of α-KTX-3 toxin peptide will keep away from the filter region of Kv1.3 channel, as BmKTX; when residue 33(or 34) has positive electrostatic potential, the anti-parallel ß-sheet domain of α-KTX-3 toxin peptide will interact with the filter region of Kv1.3 channel, as BmKTX-D33H. Above all, electrostatic potential differences on toxin surfaces and correlations motions within the toxins will determine the toxin-potassium channel interaction model. In addition, the hydrogen bond interaction is the pivotal factor for the Kv1.3-Kaliotoxin association. Understanding the binding mechanism of toxin-potassium channel will facilitate the rational development of new toxin analogue.Communicated by Ramaswamy H. Sarma.

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.

Exploring the Mechanism of the Palladium-Catalyzed 3-Butene-2-ol Amination Reaction: A DFT Study.

Palladium-catalyzed asymmetric allylic substitution, due to its valuable reactive profile, has become a quite useful tool in organic synthesis fields. In the present study, density functional theory (DFT) calculations were applied to investigate the important factors for palladium-catalyzed 3-butene-2-ol and methylaniline amination reaction, with tetrahydrofuran (THF) as solvent. We find that this catalytic protocol results in high regio- and stereoselectivity, which is in line with the experimental result. According to our calculations, the high regio- and stereoselectivity is caused by the steric hindrance between the substrate and the catalyst ligand. To verify this point, we further explore the reactive process with different axial chirality on the catalyst ligand (altering the steric hindrance), and the results suggest that the preponderant R chiral configuration product has reversed. These results could lead to a better understanding of the mechanism for 3-butene-2-ol amination reaction and are helpful for the design of the corresponding catalyst ligand in the industry.

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.

Global accurate diabatic potential surfaces for the reaction H + Li2.

The adiabatic potential energies for the lowest three states of a Li2H system are calculated with a high level ab initio method (MCSCF/MRCI) with a large basis set (aV5Z). The accurate three dimensional B-spline fitting method is used to map the global adiabatic potential energy surfaces, using the existing adiabatic potential energies, for the lowest two adiabatic states of the title reaction system. The different vibrational states and corresponding energies are studied for the diatomic molecule of reactant and products. In order to clearly understand the nonadiabatic process, the avoided crossing area and conical intersection are carefully studied. For further study of the nonadiabatic dynamic reaction, the diabatic potential energy surfaces are deduced in the present work.

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.