Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure–activity relationships and molecular docking

One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r ² = 0.878, q ² = 0.630, and r _pred² = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer’s disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3α inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3α and GSK-3β isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the β isoform are the same in the α isoform, except that Asp133 in the β isoform is replaced by Glu196 in the α isoform. We prepared a homology model for GSK-3α, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the β isoform, and helped to explain the difference in their inhibitory activity.     

Vibrational spectral analysis of structural modifications of Cr2O3 containing oxyfluoroborate glasses

Infrared and Raman spectra of oxyfluoroborate glasses of the compositions 20CaF₂-20 ZnO-(60-x) B₂O₃-x Cr₂O₃ with 0 ≤ × ≤ 0.10 mol% (x = 0, 0.02, 0.04, 0.05, 0.06, 0.07, 0.08 and 0.1) have been analyzed in order to explain the role of Cr₂O₃ on the structure of these glasses. Density, molar volume, oxygen molar volume and oxygen packing density are determined to explain the packing of the atoms in the glasses. From these studies, the existence of different borate groups like di-, tri-, tetra-, penta-, ortho-, pyro- and metaborates in these glasses is established. With the increase in the concentration of Cr₂O₃ up to 0.06 mol%, conversion of BO₃ units into BO₄ units and above this mole fraction the reconversion of BO₄ units into BO₃ units is observed. The breaking and reforming of the boroxol ring is explained from the Raman spectral studies of these glasses.     

New classes of carborane-appended 5-thio-D-glucopyranose derivatives

A series of carborane-appended 5-thio-D-glucopyranose (5-TDGP) derivatives containing one to two 5-TDGP moieties were synthesized via click cycloaddition reaction as well as following the traditional methods. Among the carboranyl-5-TDGP derivatives, the decapitated nido-carboranyl derivative 18 was found to be highly water-soluble and therefore its preliminary biodistribution study was conducted. A comparative biological evaluation of 18 versus its carboranyl-D-glucopyranose analog 19 with human hepatocellular carcinoma cells (SK-Hep1) indicated 5-TDGP to be a better boron carrier than normal D-glucopyranose. The carboranyl-5-TDGP 18 showed a nearly two fold increase in cellular boron accumulation than carboranyl-D-glucopyranose analog 19 over a period of 2 h. The accumulation of both 18 and 19 was found to occur in a temperature dependent manner. The higher accumulation of 18 suggested excellent promise for it to be a candidate for further evaluation as a future BNCT agent.     

Orientational correlations in the glacial state of triphenyl phosphite

Spallation neutron and high-energy X-ray diffraction experiments have been performed to investigate the local structure of the glacial and supercooled liquid states in triphenyl phosphite. The observed diffraction patterns have been interpreted using a Reverse Monte Carlo modeling technique. The results show that the glacial state forms unusually weak intermolecular hydrogen bonds between an oxygen atom connected to a phenyl ring and an adjacent phenyl ring aligned in an approximately antiparallel configuration. The structure is very different from the hexagonal crystal which is characterized by two weaker hydrogen bonds between linear arrays of molecules which are offset from each other and packed in a hexamer arrangement.     

Enhanced diastereoselectivity in beta-mannopyranosylation through the use of sterically minimal propargyl ether protecting groups

[reaction: see text] 2-O-Propargyl ethers are shown to be advantageous in the 4,6-O-benzylidene acetal directed beta-mannosylation reaction. The effect is most pronounced when the O3 protecting group is a bulky silyl ether or a glycosidic bond; however, even with a 3-O-benzyl ether, the use of a 2-O-propargyl ether results in a significant increase in diastereoselectivity. The beneficial effect of the propargyl ether is thought to be a combination of its minimal steric bulk, as determined by a measurement of the steric A-value and of its moderately disarming nature, as reflected in the pKa of propargyl alcohol. Conversely, the application of a 3-O-propargyl ether in the benzylidene acetal directed mannosylation has a detrimental effect on stereoselectivity, for which no explanation is at present available. Deprotection is achieved by base-catalyzed isomerization of the propargyl ether group to the corresponding allenyl ether, followed by oxidative cleavage with N-methylmorpholine N-oxide and catalytic osmium tetroxide.     

Improving the adaptability in automated vessel scheduling in container ports using intelligent software agents

Faster turnaround time of vessels and high berth productivity are paramount factors in container terminals for assuring competitive advantage in the shipping industry. An autonomous decision-making capability in the terminal is vital in achieving the required productivity. Vessel scheduling/berthing system in a container terminal is regarded as a very complex dynamic application in today’s business world. The Artificial Intelligence (AI) community has been researching in the field of intelligent (or rational) agents for more than a decade and implementations are found in many commercial applications. The Beliefs, Desires and Intention (BDI) agent architecture is probably the most mature model for many industrial applications in today’s context. However, it is not the best agent model for complex applications that must learn and adapt their behaviours in making rational decisions. We propose a new hybrid BDI framework with an intelligent module to overcome the limitations in the generic BDI model. Learning and the adaptability of the environments are assured with the introduction of the Knowledge Acquisition Module (KAM) in the generic BDI architecture in our proposed framework. The dynamic selection of the intention structures has been improved with a trained neural network. The knowledge required to handle vagueness or uncertainty in the environment has been modelled with an Adaptive Neuro Fuzzy Inference System (ANFIS) in berths. Finally, the benefits and the usability of hybrid BDI model for a vessel berthing application is discussed with experiential results.     

Noise characteristics of tractors and health effect on farmers

An investigation was conducted to determine the noise propagation (under stationary condition) and noise at operator’s ear level of popular 18.7 and 26.1 kW tractors and 4.6 and 6.7 kW hand tractors during field operations with various implements. It was observed that both tractors produced the noise of 92 dB(A) L_eq in the working zone of operator. The sound pressure level (SPL) of the hand tractor was about 2 dB(A) L_eq higher than that of the tractor. The SPL during field operations at operator’s ear level increased with increase in engine speed and forward speed. Furthermore, the SPL was higher for field operations corresponding to the implement requiring higher draft. It was observed that the SPLs of the tractors and hand tractors were more than the exposure limit of noise for 8-h workday recommended by ISO and OSHA. This may cause health problems to the farmers in the long run.