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981.
Yongtao Xu Baoyi Fan Yunlong Gao Yifan Chen Di Han Jiarui Lu Taigang Liu Qinghe Gao John Zenghui Zhang Meiting Wang 《Molecules (Basel, Switzerland)》2022,27(23)
Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors. 相似文献
982.
Yun Zhu Michael Stollenz Samuel R. Zarcone Sugam Kharel Hemant Joshi Nattamai Bhuvanesh Joseph H. Reibenspies John A. Gladysz 《Chemical science》2022,13(45):13368
The diphosphine complexes cis- or trans- PtCl2(P((CH2)n)3P ) (n = b/12, c/14, d/16, e/18) are demetalated by MC X nucleophiles to give the title compounds (P((CH2)n)3)P (3b–e, 91–71%). These “empty cages” react with PdCl2 or PtCl2 sources to afford trans- MCl2(P((CH2)n)3P ). Low temperature 31P NMR spectra of 3b and c show two rapidly equilibrating species (3b, 86 : 14; 3c, 97 : 3), assigned based upon computational data to in,in (major) and out,out isomers. These interconvert by homeomorphic isomerizations, akin to turning articles of clothing inside out (3b/c: ΔH‡ 7.3/8.2 kcal mol−1, ΔS‡ −19.4/−11.8 eu, minor to major). At 150 °C, 3b, c, e epimerize to (60–51) : (40–49) mixtures of (in,in/out,out) : in,out isomers, which are separated via the bis(borane) adducts 3b, c, e·2BH3. The configurational stabilities of in,out-3b, c, e preclude phosphorus inversion in the interconversion of in,in and out,out isomers. Low temperature 31P NMR spectra of in,out-3b, c reveal degenerate in,out/out,in homeomorphic isomerizations (ΔG‡Tc 12.1, 8.5 kcal mol−1). When (in,in/out,out)-3b, c, e are crystallized, out,out isomers are obtained, despite the preference for in,in isomers in solution. The lattice structures are analyzed, and the D3 symmetry of out,out-3c enables a particularly favorable packing motif. Similarly, (in,in/out,out)-3c, e·2BH3 crystallize in out,out conformations, the former with a cycloalkane solvent guest inside.It’s not a magic trick. Molecules can turn themselves inside out, just like articles of clothing or other familiar household objects. This behavior is demonstrated for the title compounds through a combination of synthesis, rate, and NMR studies. 相似文献
983.
Longlong Ren Zhenxiang Jing Fei Xia John Zenghui Zhang Yang Li 《Molecules (Basel, Switzerland)》2022,27(14)
Numerous experiments have revealed that fullerene (C60) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β2-adrenergic receptor (β2AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β2AR through hydrophobic interactions and π–π stacking interactions. In the C60_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β2AR. The hydroxyl groups of fullerene derivatives (C60(OH)X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β2AR. The hydroxyl groups firmly grasp the β2AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β2AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C60 did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity. 相似文献
984.
Cu3Ti原子簇结构与光谱的密度泛函理论研究 总被引:3,自引:0,他引:3
异核金属合金是非常重要的材料,Cu3Ti具有形状记忆、高强度和声音吸收特性。由于实验中只观察到一条拉曼谱线,但其稳定结构并不清晰。文章利用密度泛函理论中的SVWN5,B3LYP和BPW91方法,分别采用lanl2dz,6-31g,6-311g,6-311g(d),6-311 g(2df)和6-311 g(3d2f)基组对Cu3Ti多种可能的结构和振动光谱进行了研究。结合实验结果分析,表明其基态为自旋多重度为4的e型C2v对称性结构,基组对于频率和原子间距的影响比较大;并与实验拉曼光谱进行了对比。 相似文献
985.
986.
Kuo-yuan Hung Renata Kowalczyk Ami Desai Margaret A. Brimble John F. Marshall Paul W. R. Harris 《Molecules (Basel, Switzerland)》2022,27(14)
A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in blood caused by rapid renal excretion and its reported high susceptibility to serum proteases. The incorporation of poly (ethylene glycol) chains, coined PEGylation, is a well-established approach to improve the pharmacokinetic properties of drug molecules. Here, we report a systematic study on the incorporation of a varying number of ethylene glycol units (1–20) into the A20FMDV2 peptide to establish the effects of PEGylation size on the peptide stability in both rat serum and human plasma. In addition, the effect of acetyl and propionyl PEGylation handles on peptide stability is also described. Selected peptide analogues were assessed for integrin-αvβ6-targeted binding, showing good specificity and activity in vitro. Stability studies in rat serum established that all of the PEGylated peptides displayed good stability, and an A20FMDV2 peptide containing twenty ethylene glycol units (PEG20) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG2 and PEG5) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6. 相似文献
987.
988.
Steven Elder John Graham Roberson James Warren Robert Lawson Daniel Young Sean Stokes Matthew K. Ross 《Molecules (Basel, Switzerland)》2022,27(12)
In this study, kartogenin was incorporated into an electrospun blend of polycaprolactone and poly(lactic-co-glycolic acid) (1:1) to determine the feasibility of this system for sustained drug delivery. Kartogenin is a small-molecule drug that could enhance the outcome of microfracture, a cartilage restoration procedure, by selectively stimulating chondrogenic differentiation of endogenous bone marrow mesenchymal stem cells. Experimental results showed that kartogenin did not affect the electrospinnability of the polymer blend, and it had negligible effects on fiber morphology and scaffold mechanical properties. The loading efficiency of kartogenin into electrospun membranes was nearly 100%, and no evidence of chemical reaction between kartogenin and the polymers was detected by Fourier transform infrared spectroscopy. Analysis of the released drug using high-performance liquid chromatography–photodiode array detection indicated an abundance of kartogenin and only a small amount of its major hydrolysis product. Kartogenin displayed a typical biphasic release profile, with approximately 30% being released within 24 h followed by a much slower, constant rate of release up to 28 days. Although additional development is needed to tune the release kinetics and address issues common to electrospun scaffolds (e.g., high fiber density), the results of this study demonstrated that a scaffold electrospun from biodegradable synthetic polymers is a suitable kartogenin delivery vehicle. 相似文献
989.
990.
Nikita Brodyagin Aubrey L. Maryniak Ilze Kumpina John M. Talbott Dr. Martins Katkevics Prof. Dr. Eriks Rozners Prof. Dr. James A. MacKay 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(13):4332-4335
Peptide nucleic acids (PNA) with extended isoorotamide containing nucleobases ( I o ) were designed for binding A–U base pairs in double-stranded RNA. Isothermal titration calorimetry and UV thermal melting experiments revealed improved affinity for A–U using the Io scaffold in PNA. PNAs having four sequential Io extended nucleobases maintained high binding affinity. 相似文献