Selection of in silico drug screening results for G-protein-coupled receptors by using universal active probes

We developed a new protocol for in silico drug screening for G-protein-coupled receptors (GPCRs) using a set of "universal active probes" (UAPs) with an ensemble docking procedure. UAPs are drug-like compounds, which are actual active compounds of a variety of known proteins. The current targets were nine human GPCRs whose three-dimensional (3D) structures are unknown, plus three GPCRs, namely β(2)-adrenergic receptor (ADRB2), A(2A) adenosine receptor (A(2A)), and dopamine D3 receptor (D(3)), whose 3D structures are known. Homology-based models of the GPCRs were constructed based on the crystal structures with careful sequence inspection. After subsequent molecular dynamics (MD) simulation taking into account the explicit lipid membrane molecules with periodic boundary conditions, we obtained multiple model structures of the GPCRs. For each target structure, docking-screening calculations were carried out via the ensemble docking procedure, using both true active compounds of the target proteins and the UAPs with the multiple target screening (MTS) method. Consequently, the multiple model structures showed various screening results with both poor and high hit ratios, the latter of which could be identified as promising for use in in silico screening to find candidate compounds to interact with the proteins. We found that the hit ratio of true active compounds showed a positive correlation to that of the UAPs. Thus, we could retrieve appropriate target structures from the GPCR models by applying the UAPs, even if no active compound is known for the GPCRs. Namely, the screening result that showed a high hit ratio for the UAPs could be used to identify actual hit compounds for the target GPCRs.     

Synthesis and mesomorphic properties of new chiral banana‐shaped liquid crystals with chiral 3‐(alkoxy)propoxy terminal groups

New chiral banana‐shaped liquid crystals with chiral 3‐(alkoxy)propoxy terminal groups (Pn‐O‐PIMB5*‐4O, n = 7, 8, 9 and 10) were synthesized and their mesomorphic properties and phase structures investigated by means of electro‐optic measurements, polarizing optical microscopy, differential scanning calorimetry, and second harmonic generation measurements. Most of these chiral bent‐core mesogens (n = 7–9) showed the antiferroelectric B2 phase, whereas P10‐O‐PIMB5*‐4O exhibited the B7 phase. Comparing with the previously reported homologue Pn‐O‐PIMB(n‐2)*, we conclude that the terminal chain structure, particularly the position of chiral centres, plays an important role in the emergence of particular phase structures.     

Nuclear radii of Na and Mg isotopes

The effective root-mean-square (rms) matter radii of ^ANa (A = 20–23, 25–32) and ^AMg (A = 20, 22, 23, 27, 29–32) have been deduced from the measured interaction cross sections using a Glauber-type calculation. It was found that the increase of rms matter radii in Na isotopes is primarily a consequence of the increase of rms neutron radii. A correlation between the radii, corrected for quadrupole deformation, and the Fermi-energy difference was observed for both Na and Mg isotopes. This correlation can be explained by a model that assumes the valence nucleons are responsible for the changes in nuclear radii. The presence of a neutron skin is suggested for neutron-rich Na and Mg isotopes. An application to the nuclear equation of state (EOS) is discussed.     

Variation of free‐energy landscape of the p53 C‐terminal domain induced by acetylation: Enhanced conformational sampling

The C‐terminal domain (CTD) of tumor suppressor protein p53 is an intrinsically disordered region that binds to various partner proteins, where lysine of CTD is acetylated/nonacetylated and histidine neutralized/non‐neutralized. Because of the flexibility of the unbound CTD, a free‐energy landscape (FEL) is a useful quantity for determining its statistical properties. We conducted enhanced conformational sampling of CTD in the unbound state via virtual system coupled multicanonical molecular dynamics, in which the lysine was acetylated or nonacetylated and histidine was charged or neutralized. The fragments were expressed by an all‐atom model and were immersed in an explicit solvent. The acetylation and charge‐neutralization varied FEL greatly, which might be convenient to exert a hub property. The acetylation slightly enhanced alpha‐helix structures that are more compact than sheet/loop conformations. The charge‐neutralization produced hairpins. Additionally, circular dichroism experiments confirmed the computational results. We propose possible binding mechanisms of CTD to partners by investigating FEL. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Cubic phases of 4'-n-alkoxy-3'-nitrobiphenyl-4-carboxylic acids (ANBC-n)

The structure of the thermotropic cubic phases of 4'-ⁿ-alkoxy-3'-nitrobiphenyl-4-carboxylic acids (ANBC-ⁿ, where ⁿ indicates the number of carbon atoms in the alkoxy group) was studied by X-ray diffraction. For the homologues with ⁿ = 15, 16, 17, and 18, the cubic phase was of an ^Ia3^d type, whereas the homologues with ⁿ = 19, 20, and 21 exhibited an ^Im3^m cubic structure; for these seven homologues the same type of cubic structure was observed both on heating and cooling. Further lengthening of the alkoxy chain to ⁿ = 22 and 26, however, gave two types of cubic structure in the cubic phase region on heating, one with ^Im3^m symmetry in the low temperature region and the other with ^Ia3^d symmetry in the high temperature region. On cooling, the two homologues exhibited the ^Ia3^d cubic structure only. This is the first example in the cubic phase region of a series of homologues containing two types of structure, dependent on temperature and ⁿ. Such a complicated phase diagram in the cubic region is clearly understood qualitatively in terms of Gibbs free energy-temperature diagrams. The dependence of structural parameters such as the cubic lattice constant on the alkoxy chain length ⁿ are also presented and discussed.     

Cubic phases of binary systems of 4'-n-tetradecyloxy-3'-nitrobiphenyl-4-carboxylic acid (ANBC-14)-n-alkane

The phase behaviour of the binary systems 4'-ⁿ-tetradecyloxy-3'-nitrobiphenyl-4-carboxylic acid (ANBC-14)-ⁿ-alkane (ⁿ-tetradecane or ⁿ-hexadecane) was investigated by differential scanning calorimetry, polarizing optical microscopy, and X-ray diffraction. The phase behaviour was a function of temperature (^T) and the effective carbon number of the system (^n*), where ^n* involves carbon atoms both from the alkoxy group of ANBC-14 and from the ⁿ-alkane added. ANBC-14 shows no cubic phase, but the addition of ⁿ-alkane induced cubic phases when ^n*≧c. 15. An interesting point is that the type of cubic phase is ^Ia3^d for 15^≦n*≦17, while an ^Im3^m type is formed for 18^≦n*≦20. Furthermore, for ^n* = 22, two types of cubic phase, one with ^Im3^m symmetry in the low temperature region and the other with ^Ia3^d in the high temperature region, were observed both on heating and cooling. The phase diagram with respect to ^T and ^n* is very similar to that of pure one-component ANBC-ⁿ, which is a function of ^T and the number of carbon atoms in the alkoxy group ⁿ.