An accurate and efficient energy model to compute free energies of ligand binding to proteins is essential to understanding protein-ligand interactions, particularly to structure-based drug design. A bottleneck to derive such an energy model is how to account for the solvent effect. A grid-based free energy model was proposed (Zou et al.

An accurate and fast evaluation of the electrostatics in ligand-protein interactions is crucial for computer-aided drug design. The pairwise generalized Born (GB) model, a fast analytical method originally developed for studying solvation of organic molecules, has been widely applied to macromolecular systems, including ligand-protein complexes. Yet, this model involves several empirical scaling parameters, which have been optimized for solvation of organic molecules, peptides and nucleic acids, but not for energetics of ligand binding. Studies have shown that a good solvation energy does not guarantee a correct model of solvent-mediated interactions. Thus in this study, we have used the Poisson-Boltzmann (PB) approach as a reference to optimize the GB model for studies of ligand-protein interactions. Specifically, we have employed the pairwise descreening approximation proposed by Hawkins et al [1] for GB calculations, and DelPhi for PB calculations. The AMBER all-atom force field parameters have been used in this work. Seventeen protein-ligand complexes have been used as a training database, and a set of atomic descreening parameters has been selected with which the pairwise GB model and the PB model yield comparable results on atomic Born radii, the electrostatic component of free energies of ligand binding, and desolvation energies of the ligands and proteins. The energetics of the fifteen test complexes calculated with the GB model using this set of parameters also agrees well with the energetics calculated with the PB method. This is the first time that the GB model is parameterized and thoroughly compared with the PB model for the electrostatics of ligand binding.

Purpose We have recently reported that ultrasound imaging, together with ultrasound tissue characterization (UTC), can provide quantitative assessment of radiation-induced normal-tissue toxicity. This study’s purpose is to evaluate the reliability of our quantitative ultrasound technology in assessing acute and late normal-tissue toxicity in breast cancer radiotherapy. Method and Materials Our ultrasound technique analyzes radio-frequency echo signals and provides quantitative measures of dermal, hypodermal, and glandular-tissue toxicities. To facilitate easy clinical implementation, we further refined this technique by developing a semi-automatic ultrasound-based toxicity assessment tool (UBTAT). Seventy-two ultrasound studies of 26 patients (720 images) were analyzed. Images of 8 patients were evaluated for acute toxicity (<6 months post radiotherapy) and those of 18 patients were evaluated for late toxicity (≥6 months post radiotherapy). All patients were treated according to a standard radiotherapy protocol. To assess intra-observer reliability, one observer analyzed 720 images in UBTAT and then repeated the analysis 3 months later. To assess inter-observer reliability, three observers (two radiation oncologists and one ultrasound expert) each analyzed 720 images in UBTAT. An intraclass correlation coefficient (ICC) was used to evaluate intra- and inter-observer reliability. Ultrasound assessment and clinical evaluation were also compared. Results Intra-observer ICC was 0.89 for dermal toxicity, 0.74 for hypodermal toxicity, and 0.96 for glandular-tissue toxicity. Inter-observer ICC was 0.78 for dermal toxicity, 0.74 for hypodermal toxicity, and 0.94 for glandular-tissue toxicity. Statistical analysis found significant changes in dermal (p < 0.0001), hypodermal (p=0.0027), and glandular-tissue (p < 0.0001) assessments in the acute toxicity group. Ultrasound measurements correlated with clinical RTOG toxicity scores of patients in the late toxicity group. Patients with RTOG grade 1 or 2 had greater ultrasound-assessed toxicity percentage changes than patients with RTOG grade 0. Conclusion Early and late radiation-induced effects on normal tissue can be reliably assessed using quantitative ultrasound.

A metal-free and efficient visible-light-induced spirocyclization of indolyl-ynones with diselenides at room temperature under air atmosphere to prepare 3-selenospiroindolenines in moderate to good yields has been developed. The resulting products were tested for in vitro anticancer activity by MTT assay, and compounds 3 c and 3 e showed potent cancer cell-growth inhibition activities.

Phosphomannomutase/phosphoglucomutase occupies a central position in the pathways by which several virulence factors are synthesized in Pseudomonas aeruginosa. Virtual screening was used to identify potential inhibitors of phosphomannomutase/ phosphoglucomutase, and one compound, the anthraquinone-based dye Disperse Blue 56, showed potent inhibition in vitro. The kinetics of inhibition was complex; the time courses for reactions in the presence of the inhibitor were biphasic, suggestive of slow-binding inhibition. Quantitative analysis of the progress curves and preincubation experiments demonstrated that slow-binding inhibition was not occurring, however. Initial velocity kinetic studies indicated that Disperse Blue 56 was a parabolic, noncompetitve inhibitor. Progress curves for reactions in the presence of Disperse Blue 56 could be fitted very well by a model in which 2 equiv of the inhibitor bound to free enzyme or the enzyme-substrate complex. The inhibition was largely relieved by the inclusion of 0.01% Triton X-100 in the assay solutions, which has been suggested to be the hallmark for inhibition by compounds that exert their effect through aggregates [McGovern, S. L., Caselli, E., Grigorieff, N., and Shiochet, B. K. (2002) J. Med. Chem. 45, 1712-1722]. Our kinetic data appear to be consistent with either inhibition by a dimer of Disperse Blue 56 or inhibition by a Disperse Blue 56 aggregate, but the latter appears much more likely. We present a detailed analysis of the system to provide further information that may help in the recognition of inhibition through aggregation.

Halloysite nanotubes (HNTs), due to their unique structures and properties, may play an important role in biomedical applications. In vitro test is usually conducted as a preliminary screening evaluation of the hemocompatibility and cytotoxicity of HNTs for its short term consuming, convenience, and less expense. In this work, HNTs were processed with anticoagulated rabbit blood to detect its blood compatibility. The result of hemolysis test shows that the hemolysis ratios are below 0.5%, indicating nonhemolysis of HNTs. Plasma recalcification time suggests that HNTs are dose-dependently contributing to blood coagulation in platelet poor plasma (PPP). The effect of platelet activation caused by HNTs was also examined by scanning electron microscopy (SEM). Meanwhile, HNTs were labeled with fluorescein isothiocyanate (FITC) to observe its intracellular distribution in A549 cells under confocal microscopy. CCK-8 test and TUNEL test of HNTs at different concentration levels were performed in vitro, respectively. Therefore, the potential usage of HNTs in medicine may be very meaningful in oral dosing, dermal application, dental uses, or medical implants.

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A simple and efficient visible‐light‐promoted selenylation/cyclization of enaminones have been realized for the practical synthesis of 3‐selanyl‐4H‐chromen‐4‐ones. This reaction is performed in the mild conditions, no transition metal catalyst or photocatalysts and no additional oxidants are required. In addition, the 3‐selanyl‐4H‐chromen‐4‐ones could be easily converted to selanyl‐functionalized pyrimidines by reacting with benzamidine substrates.