Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Å2 was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R2=0.92) with an experimental measure of hydrogen bond donor potential, Δlog Poct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility. 相似文献
Knowledge of the underlying structural response during deformation processes is essential for understanding the macroscopic mechanical response of glass. Here we present results from cold compression-decompression molecular dynamics (MD) simulations of two multicomponent borosilicate glasses, Borofloat®33 (Boro33) and N-BK7® (N-BK7). Our results suggest that the densification of these two borosilicate glasses involves different types of structural changes. The fraction of permanent densification can be correlated to the change in intermediate-range structure. By performing Voronoi analysis, we quantify the contributions to densification from different cation types in these two multicomponent borosilicate glasses, finding that 3-coordinated cations facilitate the densification process. Higher-coordinated cations are relatively stable and can even show a slight expansion in their Voronoi volume. 相似文献
The development, progression, or stabilization of the atherosclerotic plaque depends on the pro-inflammatory and anti-inflammatory macrophages. The influx of the macrophages and the regulation of macrophage phenotype, inflammatory or anti-inflammatory, are controlled by the small GTPase RhoA and its downstream effectors. Therefore, macrophages and the components of the RhoA pathway are attractive targets for anti-atherosclerotic therapies, which would inhibit macrophage influx and inflammatory phenotype, maintain an anti-inflammatory environment, and promote tissue remodeling and repair. Here, we discuss the recent findings on the role of macrophages and RhoA pathway in the atherosclerotic plaque formation and resolution and the novel therapeutic approaches. 相似文献
The shear behaviors of two multicomponent borosilicate glasses, Borofloat®33 (Boro33) and N-BK7® (N-BK7), under different pressures are investigated using molecular dynamics simulations. The addition of alkali ions lowers the yield stress and changes the pressure dependence of shear modulus. Shear-induced densification is observed in both glasses. It is found that the decreases of the oxygen-centered bond angle and the coordination number change of B are responsible for the density changes at low pressures, and the increase of 5-coordinated Si is the dominant mechanism for densification at high pressures. The average shear stresses experienced by Si and B decrease with pressure except that the flow stress of Si at the end of shear deformation in N-BK7. Moreover, the average shear stress of B is more sensitive to the applied pressures compared to Si, suggesting that B is able to relax mechanical stress more easily under pressurized-shear. By analyzing the nonaffine displacement of atoms, it is found that N-BK7 exhibits more localized plastic deformation compared to Boro33 at low pressures and the local rearrangements in both glasses become more homogeneous with increasing pressure. The mean squared nonaffine displacement curves show that alkali ions have the highest mobility induced by shear compared to the network formers and B is more mobile than Si for both glasses. We also observed that plastic deformation tends to take place around boron atoms for Boro33, whereas it occurs in the alkali-rich regions for N-BK7, indicating that these two glasses have different atomic-scale deformation mechanisms. 相似文献
In this study, in situ transmission electron microscopy is performed to study the interaction between single (monomer) and paired (dimer) Sn atoms at graphene edges. The results reveal that a single Sn atom can catalyze both the growth and etching of graphene by the addition and removal of C atoms respectively. Additionally, the frequencies of the energetically favorable configurations of an Sn atom at a graphene edge, calculated using density functional theory calculations, are compared with experimental observations and are found to be in good agreement. The remarkable dynamic processes of binary atoms (dimers) are also investigated and is the first such study to the best of the knowledge. Dimer diffusion along the graphene edges depends on the graphene edge termination. Atom pairs (dimers) involving an armchair configuration tend to diffuse with a synchronized shuffling (step-wise shift) action, while dimer diffusion at zigzag edge terminations show a strong propensity to collapse the dimer with each atom diffusing in opposite directions (monomer formation). Moreover, the data reveals the role of C feedstock availability on the choice a single Sn atom makes in terms of graphene growth or etching. This study advances the understanding single atom catalytic activity at graphene edges. 相似文献
Virtual Reality - Sketch design is generally a feasible concept within virtual reality (VR). However, VR controllers suffer from a fundamental problem that limits operability and immersion, which... 相似文献
The coconut rhinoceros beetle, Oryctes rhinoceros (Linnaeus 1758) (Coleoptera: Scarabaeidae: Dynastinae) (CRB), is endemic to tropical Asia where it damages both coconut and oil palm. A new invasion by CRB occurred on Guam in 2007 and eradication attempts failed using commonly applied Oryctes rhinoceros nudivirus (OrNV) isolates. This and subsequent invasive outbreaks were found to have been caused by a previously unrecognized haplotype, CRB-G, which appeared to be tolerant to OrNV. The male-produced aggregation pheromone of the endemic, susceptible strain of O. rhinoceros (CRB-S) was previously identified as ethyl 4-methyloctanoate. Following reports from growers that commercial lures containing this compound were not attractive to CRB-G, the aim of this work was to identify the pheromone of CRB-G. Initial collections of volatiles from virgin male and female CRB-G adults from the Solomon Islands failed to show any male- or female-specific compounds as candidate pheromone components. Only after five months were significant quantities of ethyl 4-methyloctanoate and 4-methyloctanoic acid produced by males but not by females. No other male-specific compounds could be detected, in particular methyl 4-methyloctanoate, 4-methyl-1-octanol, or 4-methyl-1-octyl acetate, compounds identified in volatiles from some other species of Oryctes. Ethyl 4-methyloctanoate elicited a strong electroantennogram response from both male and female CRB-G, but these other compounds, including 4-methyloctanoic acid, did not. The enantiomers of ethyl 4-methyloctanoate and 4-methyloctanoic acid were conveniently prepared by enzymatic resolution of the commercially-available acid, and the enantiomers of the acid, but not the ester, could be separated by gas chromatography on an enantioselective cyclodextrin phase. Using this approach, both ethyl 4-methyloctanoate and 4-methyloctanoic acid produced by male CRB-G were shown to be exclusively the (R)-enantiomers whereas previous reports had suggested male O. rhinoceros produced the (S)-enantiomers. However, re-examination of the ester and acid produced by male CRB-S from Papua New Guinea showed that these were also the (R)-enantiomers. In field trapping experiments carried out in the Solomon Islands, both racemic and ethyl (R)-4-methyloctanoate were highly attractive to both male and female CRB-G beetles. The (S)-enantiomer and the corresponding acids were only weakly attractive. The addition of racemic 4-methyloctanoic acid to ethyl 4-methyloctanoate did significantly increase attractiveness, but the addition of (R)- or (S)-4-methyloctanoic acid to the corresponding ethyl esters did not. Possible reasons for the difference in assignment of configuration of the components of the CRB pheromone are discussed along with the practical implications of these results.