Pharmacophore elucidation and 3D-QSAR analysis of a new class of highly potent inhibitors of acid ceramidase based on maximum common substructure and field fit alignment methods

Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) studies have been carried on a series of 2,4-dioxopyrimidine-1-carboxamides as acid ceramidase inhibitors. Two alignment rules for the compounds were defined using maximum common substructure and field fit. The best orientation was then searched by all-orientation search strategy, to minimize the effect of the initial orientation of the structures. The Kennard Stone algorithm was used to divide the entire set into training (25 compounds) and test (7 compounds) sets. Pharmacophore model identification was also performed using DISCOtech algorithm and refinement was carried out using GASP, to highlight important structural features that could be responsible for the inhibitory activity. All constructed models showed appropriate statistical parameters in terms of q ² and r _pred ² . Based upon the information obtained from CoMFA, CoMSIA, and developed pharmacophore pattern, some key features that may be used to design new inhibitors for acid ceramidase have been identified.     

Fracture analysis of U-notched disc-type graphite specimens under mixed mode loading

Fracture phenomenon was investigated both experimentally and theoretically for a type of coarse-grained polycrystalline graphite weakened by a U-shaped notch under mixed mode loading. First, 36 disc-type graphite specimens containing a central U-notch, so called in literature as the U-notched Brazilian disc (UNBD), were prepared for four different notch tip radii and the fracture tests were performed under mode I and mixed mode I/II loading conditions. Then, the experimentally obtained fracture loads and the fracture initiation angles were predicted by using the U-notched maximum tangential stress (UMTS) and the newly formulated U-notched mean stress (UMS) fracture criteria. Both the criteria were developed in the form of the fracture curves and the curves of fracture initiation angle, in terms of the notch stress intensity factors (NSIFs). The results showed that while the criteria could predict successfully the experimental notch fracture toughness values, the UMS criterion provides slightly better predictions than the UMTS criterion, particularly for shear-dominant deformations. Also, found in this research was that the curves of fracture initiation angle were almost identical for the two criteria which both could predict well the experimental results.     

Type II c-Met inhibitors: molecular insight into crucial interactions for effective inhibition

The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein–ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.

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Experimental and theoretical study on the kinetics and mechanism of thermal decomposition of 1,2-dichloroethane

The kinetics and mechanism for the thermal decomposition of 1,2-dichloroethane (EDC) was studied in a flow system over the temperature range of 849–1064 K and pressure range of 10–300 Torr under homogeneous conditions in a tubular quartz reactor. Gas chromatography was used to measure the concentration of products. Four-center HCl elimination was found to be the most important channel in this system. Minor products such as methane, ethylene, acetylene, chloroethane, and chloroprene were identified. Ab initio calculations at the DFT, CASMP2, and QCISD(T) levels of theory were carried out to investigate the mechanism of this system and to calculate necessary parameters to compute the rate constants of different steps. Dependence of formation of vinyl chloride on the total pressure is measured, experimentally.