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The temperature dependence of the partition coefficients of a neuropeptide, substance P (SP), in isotropic acidic bicelles was investigated by using a pulsed field gradient nuclear magnetic resonance diffusion technique. The addition of negatively charged dimyristoylphosphatidylserine to the neutral bicelle changed the SP partitioning a little, which implies that the hydrophobic interaction between the hydrophobic residues of SP and the acyl chains of lipid molecules is the major interaction while the electrostatic interaction is minor in SP binding in a lipid membrane. From the temperature dependence of the partition coefficients, thermodynamic functions were calculated. The partitioning of SP into the acidic bicelles is enthalpy-driven, as it is for small unilamellar vesicles and dodecylphosphocholine micelles, while peptide partitioning into a large unilamellar vesicle is entropy-driven. This may mean that the size of lipid membranes is a more important factor for peptide binding than the surface curvature and surface charge density.

Department of Pharmacology, College of Medicine, Yonsei University, Seoul 120-752, KoreaReceived March 14, 2012, Accepted June 4, 2012Key Words : Hydroxychalcones, Vascular endothelial growth factor (VEGF), Angiogenesis, Chick chorioal-lantoic membrane (CAM)IntroductionChalcones (1,3-diphenyl propenone), the precursors offlavonoids and isoflavonoids, are abundant in edible plants.

The activity of an antimicrobial peptide, protegrin-1 (PG-1), on lipid membranes was investigated using solidstate NMR and a new sampling method that employed mechanically aligned bilayers between thin glass plates. At 95% hydration and full hydration, the peptide respectively disrupted 25% and 86% of the aligned 1palmitoyl-2-oleoyl-sn-glycero-3-phosphotidylcholine (POPC) bilayers at a P/L (peptide-to-lipid) ratio of 1/20 under the new experimental conditions. The kinetics of the POPC bilayers disruption appeared to be diffusioncontrolled. The presence of cholesterol at 95% hydration and full hydration reduced the peptide disruption of the aligned POPC bilayers to less than 10% and 35%, respectively. A comparison of the equilibrium states of heterogeneously and homogeneously mixed peptides and lipids demonstrated the importance of peptide binding to the biomembrane for whole membrane disruption.

The NF-κB system of transcription factors plays a crucial role in inflammatory diseases, making it an important drug target. We combined quantitative structure activity relationships for predicting the activity of new compounds and quantitative dynamic models for the NF-κB network with intracellular concentration models. GFA-MLR QSAR analysis was employed to determine the optimal QSAR equation. To validate the predictability of the IKKβ QSAR model for an external set of inhibitors, a set of ordinary differential equations and mass action kinetics were used for modeling the NF-κB dynamic system. The reaction parameters were obtained from previously reported research. In the IKKb QSAR model, good cross-validated q 2 (0.782) and conventional r 2 (0.808) values demonstrated the correlation between the descriptors and each of their activities and reliably predicted the IKKβ activities. Using a developed simulation model of the NF-κB signaling pathway, we demonstrated differences in IκB mRNA expression between normal and different inhibitory states. When the inhibition efficiency increased, inhibitor 1 (PS-1145) led to long-term oscillations. The combined computational modeling and NF-κB dynamic simulations can be used to understand the inhibition mechanisms and thereby result in the design of mechanism-based inhibitors.

E-mail: chulkim@hnu.kr Received March 28, 2011, Accepted August 22, 2011The conformation of a neuropeptide, substance P (SP), in isotropic (q = 0.5) acidic bicelles was investigatedusing two-dimensional NMR techniques. By the nuclear Overhauser effect (NOE) cross peaks between SP andlong-chain lipid molecules SP was probed to bind on the flat surface of the disc-like bicelles. Structural analysisof NMR data indicated that the helical conformation of SP extended to the C-terminal region of Leu10 as wellas in the mid-region from Pro4 to Phe8. As compared with the conformations of SP bound on the sodiumdodecylsulfate (SDS) or the dodecylphosphocholine (DPC) micelles with curved surfaces, the surfacecurvature of the membrane mimics was found to be one of the major factors inducing the biologically relevantconformation of SP. The negative surface charge of the membrane is also a key factor inducing both the bindingof SP on the membrane and its biologically active structure.Key Words : Substance P, Bicelle, NMR, NOESY, Surface curvature, ConformationIntroductionSubstance P (SP) is a neuropeptide of the tachykininfamily and composed of 11 amino acid residues (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a crucial enzyme in atherosclerosis as a potential drug target. The most remarkable Lp-PLA2 inhibitory drug is Darapladib. We determined the binding pose of Darapladib to Lp-PLA2 through docking study. Darapladib formed two hydrogen bonding interactions with the side chain of Tyr160 and Gln352 and several pi-pi interactions with aromatic and aliphatic hydrophobic residues of Lp-PLA2. It is known that the dietylpropan-amine moiety of Darapladib has influence on the improvement of its oral bioavailability and we supposed this in our docking results.

(4-tosyloxy-methylcyclohexane)carboxamide, prior to the fluorination was quite inefficient with the low overall yield for the development of radiopharmaceutical due to the significant breakdown of amide bond, i.e., up to 70% of starting substrate, during the re-duction of carbomethoxy group toward WAY-100635 deriva-tive. Thereby, an efficient synthesis of

2H solid-state nuclear magnetic resonance (SSNMR) spectra of 1-palmitoyl-d31-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC_ d31) in the mixture of PG-1 and POPC_d31 lipids deposited on thin cover-glass plates. The experimental line shapes of anisotropic 2 H SSNMR spectra measured at various peptide-to-lipid (P/L) ratios were simulated reasonably by assuming the mosaic spread of bilayers containing pore structures or the coexistence of the mosaic spread of bilayers and a fast-tumbling isotropic phase. Within a few days of incubation in the hydration chamber, the pores were formed by the peptide in the POPC_d31 and POPC_d31/cholesterol membranes. However, the formation of the pores was not clear in the POPC_d31/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG) membrane. Over a hundred days after hydration, a rapidly rotating isotropic phase increased in the POPC_d31 and the POPC_d31/cholesterol membranes with the higher P/L ratios, but no isotropic phase appeared in the POPC_d31/POPG membrane. Cholesterol added in the POPC bilayer acted as a stabilizer of the pore structure and suppressed the formation of a fast-tumbling isotropic phase.

Photophysical properties of a newly-synthesized porphyrin derivative, trans-bis(ferrocene carboxylato)-(5,10,15,20-tetraphenylporphyrinato)tin(IV) [Sn(TPP)(FcCOO) 2 ] were investigated by means of steady-state and fs-time resolved laser spectroscopic techniques, and compared with those of a standard molecule, trans-dichloro(5,10,15,20-tetraphenyl-porphrinato)tin(IV) [Sn(TPP)Cl 2 ]. The fluorescence spectrum of Sn(TPP)-(FcCOO) 2 was observed to exhibit dual emission bands originating from the S 2 -state and the S 1 -state, which was greatly quenched as compared to those of Sn(TPP)Cl 2 . The fs-time resolved fluorescence and transient absorption spectroscopic measurements revealed that the fluorescence quenching is due to formation of the long-lived charge transfer state by intramolecular electron transfer from ferrocene to the S 2 -excited SnTPP in addition to the enhanced non-radiative deactivation processes.

Proton coupled carbon-13 relaxation experiment was performed to investigate the effect of vicinal protons on spin-lattice relaxation of methylene carbon-13 in n-undecane. A BIRD type pulse sequence was employed as a way to check the validity of describing the 1 3 CH 2 moiety as an isolated AX 2 spin system. The results show that the presence of vicinal protons exerts substantial influence on the relaxation of methylene carbon-13, indicating that it is not a very good approximation to treat a methylene moiety as an isolated AX 2 spin system.