Run-Ling Wang

Three new powerful oseltamivir derivatives for inhibiting the neuraminidase of influenza virus

Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the open form to the closed form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings.

Docking and Molecular Dynamics Simulations of Peroxisome Proliferator Activated Receptors Interacting with Pan Agonist Sodelglitazar

PPAR (peroxisome proliferator-activated receptor) pan agonists play a critical role in treating metabolic diseases, especially the Type-2 diabetes mellitus (T2DM). GlaxoSmithKlines sodelglitazar (GW677954) is one of the potent PPAR pan agonists, which is currently being investigated in Phase II clinical trials for the treatment of T2DM and its complications. The present study was aimed at investigation into the effect of sodelglitazar at the binding pockets of PPARs. The Schrodinger Suite program (2009) was used for the molecular docking, while the GROMACS program used for the molecular dynamics (MD) simulations. The results thus obtained showed that sodelglitazar being docked well in the active site of PPARs. It was revealed by the MD simulations that the structures of the receptors remained quite stable during the simulations and that the important AF-2 helix showed less flexibility after binding with sodelglitazar. Also, it was observed that sodelglitazar could periodically form hydrogen bonds with the AF-2 helix of PPARs to stabilize the AF-2 helix in an active conformation. Our findings have confirmed that GlaxoSmithKlines sodelglitazar can activate the PPARs, which is quite consistent with the previous biological studies.

Design Potential Selective Inhibitors for Treating Cancer by Targeting the Src Homology 2 (SH2) Domain-Containing Phosphatase 2 (Shp2) with Core Hopping Approach

Due to the vital role in many cell regulatory processes, such as cell cycle control, survival and apoptosis, as well as growth and neurotransmitter signaling, Src homology 2 (SH2) domain-containing phosphatase 2(Shp2) has attracted considerable attention for developing drugs to treat cancers. In this study, by means of the powerful core hopping technique, a novel class of inhibitors was discovered based on the compound II-B08. It was observed by molecular dynamics simulations that these novel inhibitors not only possessed the same function as II-B08 did in inhibiting Shp2, but also had stronger binding to the receptor. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new inhibitors hold high potential to become promising drug candidates for developing novel and powerful drugs for anticancer. Subsequently, in vitro evaluation of promising hits revealed a novel and selective inhibitor of Shp2.

Poly[[bis­(μ-4,4′-bipyridine-κ2N:N′)copper(I)] perchlorate 0.24-hydrate]

The title copper(I) polymeric compound, {[Cu(C10H8N2)2]ClO4·0.24H2O}n, obtained by the reaction of Cu(ClO4)2 and 4,4′-bipyridine (4,4′-bpy) under hydrothermal conditions, features a fourfold-interpenetrated diamondoid coordination framework. The asymmetric unit consists of two CuI atoms, three 4,4′-bpy ligands in general positions and two halves of two centrosymmetric 4,4′-bpy ligands, two ClO4 − anions and water molecule with a site-occupancy factor of 0.480u2005(17). The CuI atoms are in a distorted tetrahedral coordination environment and are bridged by 4,4′-bpy ligands, forming a diamondoid cationic polymeric framework that encloses two symmetry-independent channels along [100], which accommodate perchlorate anions and water molecules.

Ethyl 4-[(4-chloro-phen-oxy)meth-yl]-2-(4-nitro-phen-yl)-1,3-thia-zole-5-carboxyl-ate.

The title compound, C19H15ClN2O5S, contains two molecules (A and B) in the asymmetric unit. In molecule A, the dihedral angles between the thiazole ring and the pendant chlorobenzene and nitrobenzene rings are 72.14u2005(15) and 3.03u2005(15)°, respectively. The corresponding angles for molecule B are 45.56u2005(16) and 1.51u2005(14)°, respectively. In the crystal, both molecules form inversion dimers linked by pairs of weak C—H⋯O interactions.

1-(4-Methoxy-phen-yl)imidazolidine-2,4-dione.

In the title compound, C10H10N2O3, the dihedral angle between the benzene and imidazolidine rings is 6.0u2005(4)°, consistent with an essentially planar molecule. In the crystal, intermolecular N—H⋯O hydrogen bonding between centrosymmetrically related molecules leads to loosely associated dimeric aggregates. These are connected into a three-dimensional network by C—H⋯O interactions, as well as π–π interactions [centroid–centroid distances = 3.705u2005(3) and 3.622u2005(3)u2005Å] between the imidazolidine and benzene rings.

N,N′-Diacetyl-N′-[(4-nitro­phen­oxy)acetyl]acetohydrazide

The asymmetric unit of the title compound, C14H15N3O7, contains two independent molecules which are linked into a pseudocentrosymmetric dimer by a π–π interaction, as shown by the short distance of 3.722u2005(5)u2005Å between the centroids of the benzene rings. An extensive network of weak intermolecular C—H⋯O hydrogen bonds helps to stabilize the crystal packing.

1-(2-Hy­droxy-3,5-dimeth­oxy­phen­yl)ethanone

In title compound, C10H12O4, all of the non-H atoms lie approximately in a plane with the largest deviation being 0.061u2005(2)u2005Å. An intramolecular O—H⋯O hydrogen bond generates an S(6) ring motif. No classical intermolecular hydrogen bonding occurs, with only van der Waals forces stabilizing the crystal structure.

Methyl 3,4-bis-(cyclo-propyl-meth-oxy)benzoate.

The title compound, C16H20O4, was obtained unintentionally as the byproduct of an attempted synthesis of methyl 3-(cyclopropylmethoxy)-4-hydroxybenzoate. In the crystal, the molecules are linked by intermolecular C—H⋯O interactions.

Methyl 3-(cyclo­propyl­meth­oxy)-4-hy­droxy­benzoate. Corrigendum

Corrigendum to Acta Cryst. (2010), E66, o2004.