Structures Of Small Molecules Research Articles

In Silico Prediction of EGFR Inhibitors from Thiophene Derivatives

Abstract: Cancer is one of the biggest global health problems and is the second leading cause of death worldwide. Cancer also causes great damage to economy. Unfortunately, there is still no effective treatment method against this disease today, and the mortality rates in certain types are still very high. Medical research can now be done faster and safer with the aid of in silico studies. These studies save time for researchers and accelerate new drug discoveries. In our study, thiophene derivatives with important efficacy in cancer treatment were focused on and the affinity of the small molecule structures determined as candidates to the Epidermal Growth Factor Receptor (EGFR), known to be the key receptor in cancer, was examined. First, molecular docking studies were performed, and then long-term molecular dynamics (MD) simulations were carried out. Finally, anti-cancer activity predictions based on Quantitative Structure-Activity Relationship (QSAR) were performed. Co-crystallized ligand Erlotinib, taken from the Protein Data Bank (PDB), was used as a positive control and compared with candidate drugs using the same procedures. In light of the analysis of virtual screening, MD, MM/GBSA, and QSAR predictions, the top three molecules and their MM/GBSA scores were identified as follows: OSI 930 (-65.81 kcal/mol), Neltenexine (-49.53 kcal/mol), and Tenonitrozole (-41.95 kcal/mol). As a result, in this study, candidate molecules that inhibit EGFR and have the highest potential as anti-cancer drugs among thiophene-derived compounds were determined and detailed in silico analyzes were performed. This study holds importance as it may guide future anti-cancer drug discovery studies.

Susceptible Detection of Organic Molecules Based on C3B/Graphene and C3N/Graphene van der Waals Heterojunction Gas Sensors.

Constructing van der Waals (vdW) heterostructures is a prospective approach that is essential for developing a new generation of functional two-dimensional (2D) materials and designing new conceptual nanodevices. Using density-functional theory combined with a nonequilibrium Green's function approach allows for the theoretical and systematic exploration of the electronic structure, transport properties, and sensitivity of organic small molecules adsorbed on 2D C3B/graphene (Gra) and C3N/Gra vdW heterojunctions. Calculations show the metallic properties of C3B/Gra and C3N/Gra after the formation of heterojunctions. Interestingly, the heterojunctions C3B/Gra (C3N/Gra) for the adsorption of small organic molecules (C2H2, C2H4, CH3OH, CH4, and HCHO) at the C3B (C3N) side are sensitive to the chemisorption of C2H2 and C2H4. Similarly, the Gra/C3B is chemisorbed for both C2H2 and C2H4 when adsorbed on Gra side, while it is only chemisorbed for C2H2 in Gra/C3N. Interestingly, all heterojunctions on different sides are physisorbed for CH3OH, CH4, and HCHO. Furthermore, the calculated I-V curves demonstrate that the devices based on the adsorption of C2H2 and C2H4 at each side of the heterojunction have remarkable anisotropy, in with the current being considerably greater in the zigzag direction than in the armchair direction. More specifically, with C2H2 adsorbed on the Gra side, the sensitivity along the armchair direction is up to 85.0% for Gra/C3B and close to 100% for Gra/C3N. This study reveals that C3B/Gra (C3N/Gra) heterojunctions with high selectivity, high anisotropy, and excellent sensitivity are highly prospective 2D materials for applications, which further contributes new insights into the development of future electronic nanodevices.

Modeling protein-small molecule conformational ensembles with ChemNet.

Modeling the conformational heterogeneity of protein-small molecule systems is an outstanding challenge. We reasoned that while residue level descriptions of biomolecules are efficient for de novo structure prediction, for probing heterogeneity of interactions with small molecules in the folded state an entirely atomic level description could have advantages in speed and generality. We developed a graph neural network called ChemNet trained to recapitulate correct atomic positions from partially corrupted input structures from the Cambridge Structural Database and the Protein Data Bank; the nodes of the graph are the atoms in the system. ChemNet accurately generates structures of diverse organic small molecules given knowledge of their atom composition and bonding, and given a description of the larger protein context, and builds up structures of small molecules and protein side chains for protein-small molecule docking. Because ChemNet is rapid and stochastic, ensembles of predictions can be readily generated to map conformational heterogeneity. In enzyme design efforts described here and elsewhere, we find that using ChemNet to assess the accuracy and pre-organization of the designed active sites results in higher success rates and higher activities; we obtain a preorganized retroaldolase with a k cat / K M of 11000 M -1 min - 1 , considerably higher than any pre-deep learning design for this reaction. We anticipate that ChemNet will be widely useful for rapidly generating conformational ensembles of small molecule and small molecule-protein systems, and for designing higher activity preorganized enzymes.

Computational Study of Aminoglycoside and Fluoroquinolone Antibiotics

Molecular Docking has become an important component of the drug discovery process. Since first being developed in the 1980s, advancements in the power of computer hardware and the increasing number of and ease of access to small molecule and protein structures have contributed to the development of improved methods, making docking more popular in both industrial and academic settings. In this research Molecular Docking performed on Ciprofloxacin and Streptomycin by using Auto dock and Discovery Studio Software. QSAR study revealed that substitution of different electron donating or withdrawing group at different position on Ciprofloxacin and Streptomycin. Lead nucleus elaborate change in pharmacological activity. Molecular docking done by substituting or replacing different group at different position affected the potency of drug. On addition of methyl and nitro group decreases the activity of Ciprofloxacin while replacement of Guanidino groups from streptidine ringincreases its antibiotic activity.

Enhancing electric field intensity of interfacial electric double layer to improve properties of solid electrolyte interface for sodium-ion batteries

The electrical double layer (EDL) provides a critical area, where the specific adsorption on the electrode dominates the initial structure and chemical composition of the solid electrolyte interface (SEI) film. Therefore, the SEI can be optimized by adjusting the properties of the EDL. Here, we regulate the properties of EDL to optimize the composition and morphology of the SEI film on the hard carbon anode surface by adding NaF with small molecule structure. The preferential accumulation of NaF additives on the electrode surface enhances the electric field intensity and promotes electrolyte decomposition. That is, the formed SEI film rich in inorganic NaF and B-O components, can significantly improve the storage capacity of sodium ions in the hard carbon anode and accelerate the rapid transport of sodium ions. This strategy enables the cycling capacity to improve by 13.5 %, and maintain a stable capacity retention rate of 86.2 % at the rate of 1C after 500 cycles, thereby extending the lifespan and increasing the capacity of the rechargeable battery. The strategy that utilizing small molecule additives to enhance the electric field intensity of EDL provides a new approach to improve the performances of SEI film and battery performances.

Oligomerized Acceptors with High Efficiency and Superior Stability in Organic Solar Cells.

Oligomerized small molecular acceptors (OSMAs) have rapidly become a research hotspot in the field of organic solar cells due to their advantages of effective combination with definite structure of small molecules and high viscosity and glass transition temperature of polymers. From this perspective, we classify and summarize the representative OSMAs from the three binding sites of end, core, and wing, and we summarize the exploration of new synthesis methods to improve the plights, such as low synthesis yield and difficult purification. Finally, the existing challenges and future research directions are concluded and prospected.

Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.

Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.

Fabrication and Photovoltaic Conversion Performances of Imidazolyl and Fumaric Acid Composite Langmuir-Blodgett Membranes.

Novel organic small molecule structures have received increasing attention in the preparation of multifunctional thin film materials and have become the subject of research in many cutting-edge directions. In this work, imidazolyl and transbutylene glycolic acid molecules and dye molecules were designed and prepared as composite films by supramolecular self-assembly in the LB technique, and their morphological features and spectral properties were analyzed. The results showed that the prepared LB films presented different aggregation states. In addition, their photoelectrochemical properties, on ITO sheets were tested, all of which showed good optoelectronic properties, and their binding energies, structure optimization, and electrostatic potentials were theoretically calculated by DFT simulations, which proved that the prepared films have good optoelectronic properties, and have the potential to become optoelectronic multifunctional ultrathin film devices.

A Kaczmarz-inspired approach to accelerate the optimization of neural network wavefunctions

Neural network wavefunctions optimized using the variational Monte Carlo method have been shown to produce highly accurate results for the electronic structure of atoms and small molecules, but the high cost of optimizing such wavefunctions prevents their application to larger systems. We propose the Subsampled Projected-Increment Natural Gradient Descent (SPRING) optimizer to reduce this bottleneck. SPRING combines ideas from the recently introduced minimum-step stochastic reconfiguration optimizer (MinSR) and the classical randomized Kaczmarz method for solving linear least-squares problems. We demonstrate that SPRING outperforms both MinSR and the popular Kronecker-Factored Approximate Curvature method (KFAC) across a number of small atoms and molecules, given that the learning rates of all methods are optimally tuned. For example, on the oxygen atom, SPRING attains chemical accuracy after forty thousand training iterations, whereas both MinSR and KFAC fail to do so even after one hundred thousand iterations.

Preparation of Highly-Ordered Tetrabenzorporphyrin Films Controlled by Supramolecular Assemblies and Precursor Approach

The control of the orientation and packing structures of small organic semiconductor molecules is the important issue for the improvement of charge carrier mobilities of organic field effect transistors. Tetrabenzoporphyrin (BP) is one of the promising p-type organic semiconductors but solubility in organic solvents is very low. We have developed a precursor approach, where a spun-cast film of soluble precursor, tetra-bicyclo[2.2.2]octadiene-fused porphyrin (CP), was heated to obtain BP crystalline film by in-situ retro-Diels–Alder reaction. However, the obtained BP film is a polycrystalline film and the field-effect transistors (FETs) hole mobilities were 10-1~10-2 cm2V-1s-1[1]. Recently, we reported the effect of alkyl substituents at 5,15-positions of BP for the control of the molecular arrangement. The best performance of OFET hole mobility of 5,15-disubstituted BP was 4.1 cm2V-1s-1 [2, 3].A supramolecular strategy has attracted attentions as the effective method for the control of molecular arrangement in films. We applied the combination of supramolecular assembling method and the precursor approach to prepare well-ordered BP films. 5,15-Bis(p-dodecylamidephenyl)-CP was deposited on the substrate by drop-casting, spin-coating or dip-coating method, followed by the heating to 200 ºC for 10 min to give the corresponding 5,15-bis(p-dodecylamidephenyl)-BP films. The film morphologies of the BP were compared with 5,15-bis(p-dodecyloxyphenyl)-BP, which doesn’t include amide moieties for hydrogen-bonding, using UV-vis absorption spectroscopy, atomic force microscopy (AFM), X-ray diffraction (XRD) analysis, and p-polarized multiple-angle incidence resolution spectrometry (p-MAIRS) to clarify the effect of amide groups. OFET performance of the BPs will be also discussed to clarify the effect of intermolecular hydrogen bonding interaction.

Fast Event-Based Electron Counting for Small Molecule Structure Determination by MicroED

Fast Event-Based Electron Counting for Small Molecule Structure Determination by MicroED

Structural Comparison of Substrate Binding Sites in Dehaloperoxidase A and B.

Dehalperoxidase (DHP) has diverse catalytic activities depending on the substrate binding conformation, pH, and dynamics in the distal pocket above the heme. According to our hypothesis, the molecular structure of the substrate and binding orientation in DHP guide enzymatic function. Enzyme kinetic studies have shown that the catalytic activity of DHP B is significantly higher than that of DHP A despite 96% sequence homology. There are more than 30 substrate-bound structures with DHP B, each providing insight into the nature of enzymatic binding at the active site. By contrast, the only X-ray crystallographic structures of small molecules in a complex with DHP A are phenols. This study is focused on investigating substrate binding in DHP A to compare with DHP B structures. Fifteen substrates were selected that were known to bind to DHP B in the crystal to test whether soaking substrates into DHP A would yield similar structures. Five of these substrates yielded X-ray crystal structures of substrate-bound DHP A, namely, 2,4-dichlorophenol (1.48 Å, PDB: 8EJN), 2,4-dibromophenol (1.52 Å, PDB: 8VSK), 4-nitrophenol (2.03 Å, PDB: 8VKC), 4-nitrocatechol (1.40 Å, PDB: 8VKD), and 4-bromo-o-cresol (1.64 Å, PDB: 8VZR). For the remaining substrates that bind to DHP B, such as cresols, 5-bromoindole, benzimidazole, 4,4-biphenol, 4.4-ethylidenebisphenol, 2,4-dimethoxyphenol, and guaiacol, the electron density maps in DHP A are not sufficient to determine the presence of the substrates, much less their orientation. In our hands, only phenols, 4-Br-o-cresol, and 4-nitrocatechol can be soaked into crystalline DHP A. None of the larger substrates were observed to bind. A minimum of seven hanging drops were selected for soaking with more than 50 crystals screened for each substrate. The five high-quality examples of direct comparison of modes of binding in DHP A and B for the same substrate provide further support for the hypothesis that the substrate-binding conformation determines the enzyme function of DHP.

NMR structures of small molecules bound to a model of an RNA CUG repeat expansion.

Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)exp. The RNA folds into a hairpin structure with a periodic array of 1×1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function. Here, we report NMR-refined structures of single 5'CUG/3'GUC motifs in complex with three different small molecules, a di-guandinobenzoate (1), a derivative of 1 where the guanidino groups have been exchanged for imidazole (2), and a quinoline with improved drug-like properties (3). These structures were determined using nuclear magnetic resonance (NMR) spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1, 2, and 3 formed stacking and hydrogen bonding interactions with the 5'CUG/3'GUC motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)exp. As the first ever reported structures of RNA r(CUG) repeats bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.

Accelerating Molecular Docking using Machine Learning Methods.

Virtual screening (VS) is one of the well-established approaches in drug discovery which speeds up the search for a bioactive molecule and, reduces costs and efforts associated with experiments. VS helps to narrow down the search space of chemical space and allows selecting fewer and more probable candidate compounds for experimental testing. Docking calculations are one of the commonly used and highly appreciated structure-based drug discovery methods. Databases for chemical structures of small molecules have been growing rapidly. However, at the moment virtual screening of large libraries via docking is not very common. In this work, we aim to accelerate docking studies by predicting docking scores without explicitly performing docking calculations. We experimented with an attention based long short-term memory (LSTM) neural network for an efficient prediction of docking scores as well as other machine learning models such as XGBoost. By using docking scores of a small number of ligands we trained our models and predicted docking scores of a few million molecules. Specifically, we tested our approaches on 11 datasets that were produced from in-house drug discovery studies. On average, by training models using only 7000 molecules we predicted docking scores of approximately 3.8 million molecules with R2 (coefficient of determination) of 0.77 and Spearman rank correlation coefficient of 0.85. We designed the system with ease of use in mind. All the user needs to provide is a csv file containing SMILES and their respective docking scores, the system then outputs a model that the user can use for the prediction of docking score for a new molecule.

TransExION: a transformer based explainable similarity metric for comparing IONS in tandem mass spectrometry

Small molecule identification is a crucial task in analytical chemistry and life sciences. One of the most commonly used technologies to elucidate small molecule structures is mass spectrometry. Spectral library search of product ion spectra (MS/MS) is a popular strategy to identify or find structural analogues. This approach relies on the assumption that spectral similarity and structural similarity are correlated. However, popular spectral similarity measures, usually calculated based on identical fragment matches between the MS/MS spectra, do not always accurately reflect the structural similarity. In this study, we propose TransExION, a Transformer based Explainable similarity metric for IONS. TransExION detects related fragments between MS/MS spectra through their mass difference and uses these to estimate spectral similarity. These related fragments can be nearly identical, but can also share a substructure. TransExION also provides a post-hoc explanation of its estimation, which can be used to support scientists in evaluating the spectral library search results and thus in structure elucidation of unknown molecules. Our model has a Transformer based architecture and it is trained on the data derived from GNPS MS/MS libraries. The experimental results show that it improves existing spectral similarity measures in searching and interpreting structural analogues as well as in molecular networking.Scientific ContributionWe propose a transformer-based spectral similarity metrics that improves the comparison of small molecule tandem mass spectra. We provide a post hoc explanation that can serve as a good starting point for unknown spectra annotation based on database spectra.

Understanding the impact of thiazole unit sequence in π-bridge on the performance of small molecule donor materials

Energy level regulation and crystallization optimization of materials are the key ideas to improve the performance of organic solar cells. In this work, based on clarifying small molecule structure, we introduce thiazole into different positions of π-bridge and investigate its effect on the properties of small molecule donors (SMDs) and related device performance. As thiazole gradually moves towards BDT, the electron clouds of these three SMDs (BTTTzR, BTTzTR and BTzTTR) tend to be divided on the framework, gradually deepened the energy level, and enlarged band gaps. In terms of device performance, the BTTzTR:Y6 device shows good inhibition of charge recombination and phase separation performance, and the efficiency of the related OSCs is 7.87 %. Morphological analysis shows that BTTTzR is prone to form nanoscale microcrystals after thermal annealing treatment, with slightly decreased performance of 6.79 %. BTzTTR is affected by difficult intramolecular charge transfer and weak intermolecular interactions, shows the worst performance of 5.77 %. This work is conducive to a deeper understanding of the electron-deficient substitution of the π-bridge in SMDs.

Preparation of green biodegradable lactic acid-based flame-retardant plasticizer for simultaneously enhancing flexibility, flame retardancy, and smoke-suppression of poly(lactic acid)

Conventional petroleum-based plasticizers not only exhibit reproductive toxicity and non-biodegradability, but their introduction also makes plastics highly combustible. Therefore, the development of biodegradable flame-retardant plasticizers derived from biomass resources can effectively solve the matters mentioned above. In this work, we developed a new l-lactic acid-based biodegradable flame-retardant plasticizer containing phosphorus, nitrogen, and silicon elements (PDL550) with flame-retarded, smoke-suppressing, and plasticized function. The introduction of PDL550 can simultaneously enhance the flame-retardant and flexible performances of polylactic acid (PLA). With the addition of 20 phr PDL550, the PDL550-plasticized PLA blends could pass a UL-94 V-0 grade, and simultaneously its elongation at break increased to 290.32 % in comparison with that of pure PLA (3.70 %). The cone calorimetric tests exhibited that the peak of heat release rate and total heat release of PDL550-plasticized PLA blends, in comparison with that of pure PLA, decreased by 17.8 and 50.8 %, respectively. By analyzing the volatiles and the residual char layer, the phosphorus and silicon elements synergistically in PDL550 are conducive to facilitating the formation of the complete and dense char layer, thus suppressing the release of smoke and shielding the attack of heat. Interestingly, the active soil and tenebrio molitors experiments exhibited that the PDL550 chain was attacked by microbes to form a small aliphatic molecule structure, indicating the excellent biodegradability of PDL550. This study provides an essential reference for developing bio-derived fire-retardant plasticizers to enhance fire safety, smoke-suppressing, and flexible PLA composites.

Photo‐Assisted Bifunctional Cathodes with Lower Energy Gap and Broadened Light Absorbing Region for Lithium‐Ion Batteries – Extended Conjugation Through Customization

AbstractHigh‐performance optoelectronic bifunctional cathode materials may simultaneously seize and store solar energy in lithium‐ion batteries to boost their storage capacity. However, such photoactive cathodes with typical intrinsic features are generally limited for UV light applications and offer poor sunlight harvesting which results in lower energy density. Here, the assembly of two oligomers, poly(vat blue 6) (PVB6) and poly(vat blue 6 sulfide) (PVB6S) is reported, through polymerization to extend the conjugated structure of organic optoelectronic small molecules. These oligomers are effectively employed as photo‐assisted bifunctional cathodes for lithium‐ion batteries. The extended conjugated structure narrows the energy gap, promoting exciton dissociation and expanding the light absorption region. PVB6S possesses a narrow energy gap of 1.565 eV, and the discharge‐specific capacity of the battery with PVB6S is enhanced from 203 to 411 mAh g−1 under light illumination, which is approximately twice the original capacity. This demonstrates the extended conjugated structure and charge separation in a cell, which synergistically contributes to the rational design of photo‐assisted bifunctional cathode materials and complementary enhances the performance of lithium‐ion batteries.

Design and Preparation of Multicolor Long‐Lifetime Fluorescent Material Based on Charge‐Separated States

AbstractAfterglow materials have the advantages of long luminescent lifetime and large stokes shift, which show good application prospects in fields such as probes, anti‐counterfeiting, and organic light‐emitting diode (OLED). Nevertheless, the preparation of multicolor long afterglow materials with simple components remains a challenge. This article proposes a general strategy for preparing room temperature long‐lifetime fluorescent polymer materials. This strategy involves doping various fluorescent small molecules containing electron‐donating groups into polymers containing electron‐withdrawing groups. The results show the two components can form charge‐separated state by long‐range charge transfer, and the excitons recombined in fluorescent molecules and emitted long‐lived fluorescence. After photoactivation, the P3COMe film doped with 1% RhB can emit red fluorescent afterglow. The lifetime can achieve 39.4 ms, and the afterglow can last 4.17 s. Meanwhile, by introducing fluorescent molecules with different luminescent colors, the multicolor long‐lifetime fluorescence is also realized. In addition, the influence of the structure of luminescent small molecules on the afterglow fluorescent properties of their doped films is also elucidated.

Synthesis, structure, and small molecule in situ modification effects on proton conduction properties of triazine‐based triscarboxylic acid complexe

In this study, we synthesized and characterized a new Co(II)‐based coordination polymer, denoted as {[Co(HL)(dpa)]·H2O}n (1), derived from the H3L ligand and dpa co‐ligand. Single crystal X‐ray diffraction revealed that 1 forms a two‐dimensional (2D) layer and a three‐dimensional (3D) supramolecular structure via hydrogen bonding interactions. Presence of carboxylic acid groups in 1 was confirmed by X‐ray crystallography, prompting investigation into its proton transport properties. Additionally, electrostatic potential surface and nucleophilic index analyses were conducted to simulate potential proton transfer pathways. Furthermore, we prepared nine modified encapsulated materials using 1 as the base material (SDA@1, APH@1, APY@1, TA@1, BA@1, DIC@1, IDZ@1, SCA@1, and TYD@1), and tested their proton conductivity and activation energy compared to pure Nafion membrane and 1, analyzing the influence of different small molecule structures on proton conductivity. Comparative analysis revealed that only SDA@1 exhibited enhanced proton conductivity and reduced activation energy at 303 K, with an improvement rate of 220.8%. We hope that the methods presented herein can provide valuable insights for the design and development of high‐performance proton‐conducting materials, as well as for the exploration of proton conduction mechanisms.