Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Recurring Candida albicans esophagitis in a HIV-infected patient undergoing long-Term antiretroviral therapy, and with absent-negligible immunodeficiency.

A patient with HIV infection developed the first episode of AIDS-defining opportunism (severe Candida albicans esophagitis) with an underlying CD4+ lymphocyte count of 1,025 cells/microL. After treatment with a highly active antiretroviral therapy (HAART), taken with insufficient compliance and leaving a residual viral load, our patient suffered from two relapses of esophageal candidiasis, which occurred three months and seven years later, when his CD4+ lymphocyte count was 930 and 439 cells/microL, respectively, and a viral load slightly above 10(4) copies/mL was still present. Also in the HAART era, Candida esophagitis remains one of the most common AIDS-defining diseases, but a presentation with a concurrent CD4+ count above 1,000 cells/microL remains a rare exception, as well as the two isolated, subsequent relapses, occurred with a CD4+ count ranging from 439 to 930 cells/microL, and a residual HIV viremia due to insufficient adherence to the prescribed HAART regimens. Our case report represents the opportunity to revisit the epidemiology and, especially, the pathogenesis of this opportunistic fungal complication in HIV-infected patients and in other subjects at risk, on the ground of an extensive literature review, and to explore possible alternative supporting factors other than the crude absolute CD4+ lymphocyte count, with emphasis on the possible role of a persisting HIV viremia, and other potential contributing factors. Clinicians engaged with immunocompromised patients and subjects with HIV disease, should be aware that a Candida esophagitis may occur and relapse also when the cell-mediated immunity, as measured by a simple CD4+ cell count, do not show relevant abnormalities.     

A Spanish version of the Family Assessment Device

Introduction  

This paper presents the results of a study on the psychometric properties of an authorized Spanish version of the McMaster Family Assessment Device, a self-report measure of family functioning.     

腔内聚乙烯十二指肠-空肠导管对体重调节的作用:猪动物模型可行性研究

目的评估十二指肠-空肠导管（Endoluminal Duodeno-Jejunal Tube，EDJT）在活体猪实验动物模型中减缓体重增加的可行性，及其在中短期生存中的安全性。方法本项研究共用8只45kg重的Yorkshire猪，其中3只置入180emEDJT，1只置入360cm EDJT，另4只猪作为对照组。切开十二指肠，将EDJT导管缝合固定在十二指肠近Vater壶腹起始处。结果评估全部猪的不适反应和体重，每日一次，共7周，未发现严重并发症发生。术后7周3组动物的平均体重变化百分率：对照组、180cm组和360cm组分别是22．5％，6％和-2．8％。EDJT组（180cm组、360cm组）体重增加明显减慢，与对照组相比，有统计学意义（P=0．05）。结论EDJT可以安全使用，无肠梗阻、肠套叠或胰腺炎等并发症发生。EDJT可明显减缓体重增加。