药物分子构象对药理活性的影响——分子轨道方法的应用

本文简要叙述了药物分子构象对药物分子药理作用的影响,讨论了非平衡药物分子构象在药物分子活性中的作用。同时也介绍了分子轨道方法在研究药物分子构象中主要优点和限制,并展望分子轨道计算方法的应用前景。     

胆碱酯酶重活化剂PAM类构型、构象问题

本文参考X-衍射数据,采用MNDO程序计算了不同构型、构象PAM类的生成热,结合核磁共振数据讨论了PAM类构象等问题.结果表明,PAM类在水溶液中:顺式体肟基可以自由旋转,任何一种构象都可能成为药效构象;反式体肟基本不可能存在稳定的平面构象,其药效构象只能是优势构象.用MNDO程序中反应途径的计算法,还计算了顺、反式肟基构型相互转变的势垒,为探讨PAM类重活化机理提供了一定的参考.     

药物-受体作用的相互适应关系

药物-受体相互作用是复杂的,药物和酶的作用也与之类似,任何结构参量与活性之间的线性关系仅仅存在于一定范围之内,每个结构因素的某些微小变化都可能引起药理性质的明显改变。讨论药物构效关系及进行新药物设计时,应该多考虑药物分子的整体统一性,不必过分强调单因素的完美线性关系。提出并讨论了药物-受体之间存在相互适应原理,其中包括:空间效应与几何互补关系、构象调节与构象改变最小原理、范德华力、油水分配系数与生物活性之间的曲线关系、药物-受体分子轨道作用的适宜量值等。     

Titin蛋白PEVK片段中PVAP基序的构象研究

 目的通过构象搜索,得到Titin蛋白EVK片段中PVAP基序的低能构象.方法利用分子力学随机构象搜索法和混合MonteCarlo方法,对Titin蛋白PEVK片段中的PVAP基序进行构象搜索.结果随机构象搜索得到的低能构象集中,PVAP的构象骨架分为折叠式和伸展式,其中以折叠式为优势构象;利用混合Monte Carlo方法得到的低能构象与随机构象搜索结果基本一致.结论在拉力作用下,PVAP的构象由折叠式转变成伸展式,使分子在宏观上表现为弹性,为解释其对Titin蛋白弹性的贡献提供了一定的理论依据.     

分子力学MMPM与量子化学MNDO联算软件包

分子力学和量子化学计算是计算化学中两种基本的方法,是解决有机和药物分子结构以及阐明结构与性能关系的有力工具。物理有机化学和药物构效关系研究中,已有许多文献采用量子化学计算得到的各种分子轨道参数来进行相关分析和理论说明。但是,量子化学计算花费的机时与所计算的电子数目的4次力成正比,对于较大的有机药物分子,往往需要花费很长时间才能完成计算,不利于快出科研成果。分子力学是建立在经典力场和实验参数基础上的一种计算方法,具有直观和优化几何构象花费计算机     

抗体可变区稳定性评价及其初步应用

目的：通过研究抗体轻、重链间的结合能与其构象特征、理化性质间的内在关系,建立相应的数学模型,合理评价抗体分子的热稳定性,为抗体分子的设计、合理改造及亲和力成熟奠定基础。方法采用生物信息学和计算生物学相关方法对已有晶体结构的抗体结构信息进行分析,通过距离几何学、计算机图形学技术对抗体可变区的构象特征进行研究;基于分子间氢键形成理论、反应自由能理论,从热力学、动力学对抗体分子轻、重链可变区相互作用的动态结构及能量特征进行探讨;借助统计学原理、非线性拟合、回归分析等分析手段对抗体轻、重链作用能与其构象特征、理化性质建立相关性分析。结果通过分子模拟与统计学分析,抗体的轻、重链可变区结合能与其轻、重链间的氢键形成数目、范德华作用均存在线性相关性;与抗体理化性质存在基于多项式的非线性相关性。基于关键位置氨基酸的使用频率以及建立的分析模型,针对无法获得稳定工程细胞株的抗蓖麻毒素人源化功能抗体进行合理的评价及优化,借助理论指导,获得抗蓖麻毒素人源化抗体稳定的工程细胞株。结论抗体可变区的自身结构（构象、理化性质）对其稳定性有很大影响,可以通过抗体结构优化来提高抗体的稳定性。     

取代2H-苯并吡喃-3-甲酰苯胺化合物的合成及抗辐射活性评价

目的 发现新结构的活性分子,为抗辐射药物研究提供候选化合物。方法 使用构象固定和官能团转换策略对Ex-RAD进行结构改造,设计并合成取代2H-苯并吡喃-3-甲酰苯胺化合物。通过照射细胞存活模型进行抗辐射活性筛选,并考察活性化合物的细胞毒性。优选活性化合物进行Western印迹实验,考察对照射细胞凋亡相关蛋白表达的影响,并通过照射小鼠模型评价其抗辐射活性。结果 合成目标化合物21个,通过筛选发现8个化合物可以显著提高照射细胞的存活,选择4个化合物进行复筛和细胞毒性评价。优选化合物D19进行Western印迹实验,发现D19可以影响照射AHH-1细胞凋亡相关蛋白的表达。与辐射组相比,D19可以使全身8.6 Gy照射小鼠30 d存活率提高70%。D19对非致死剂量照射小鼠的血液系统具有保护作用。结论 新结构的化合物D19具有明确的抗辐射活性,值得进一步深入研究。     

昆虫防御素A的分子改造及其在噬菌体表面的展示

目的：实现对昆虫防御素A的分子改造及改造后分子的噬菌体表面展示，为进一步设计构象型肽库，研究分子间相互作用奠定基础。方法：分子改造包括以下内容；分子截短，突变碱性氨基酸，减少半胱氨酸的数目等。利用InsightⅡHomology系统对改造后分子结构进行预测。然后再将合成的改造蛋白基因插入到pCANTAB5E载体中，采用Western印迹鉴定该蛋白在噬菌体表面展示。结果与结论：模建结果显示改造后蛋白仍保持原有三维结构不变，并且成功实现了昆虫防御素分子在噬菌体表面的展示。     

动态增强磁共振成像在抗肿瘤血管药物早期临床试验中的应用

动态增强磁共振成像（DCE-MRI）正逐渐被应用于抗肿瘤血管药物的早期临床试验。该文将对传统临床试验药效评价体系应用于抗肿瘤血管分子靶向药物研发中所存在的问题、DCE-MRI的相应技术原理、DCE-MRI临床应用现状与其在临床试验中的优势、存在的问题与展望做一综述,并列举一些近年来应用DCE-MRI技术进行抗肿瘤血管分子靶向药物临床试验的典型案例。     

N，N－二取代甘氨酸－3－羟基－1，4－苯并二氮卓酯制备方法的MNDO研究

应用量子化学的微扰分子轨道理论，对用两种不同合成方法制备Ｎ，Ｎ－二取代甘氨酸－３－羟基－１，４－苯并二氮酯的可行性进行了分析。通过改进的忽略双原子微分重叠法（ＭＮＤＯ）程序计算，得到了原子净电荷、前线轨道电荷及前线轨道系数，代入微扰分子轨道方程后，得到了半定量的理论产率估计，该估计与实验结果基本一致。     

Effect of exercise on oxygen consumption, heart rate, and the electrocardiogram of pigs

Pigs were exercised for 5 min at five different treadmill speeds (1.0-1.8 m X s-1) (3 degrees incline), while oxygen consumption (MO2), carbon dioxide production (MCO2), and the electrocardiogram (ECG) were recorded continuously. Data were taken at rest, during exercise, and at 2, 5, 15, and 30 min after exercise. Values for MO2, MCO2, and heart rate (HR) showed progressive increases with increasing treadmill speed. The respiratory exchange ratio (R) increased during exercise and approached 1.0, but peak values were seen shortly after exercise. Heart rate, MO2, MCO2, and R reached steady-state values after 2 min of exercise, which were maintained for the duration of exercise. In most cases, these variables had returned to control levels 15 min after exercise. A high correlation between HR and MO2 was found in these animals. Prominent increases in T-wave amplitude of the ECG were associated with exercise and early recovery. The metabolic and cardiac changes associated with exercise in these animals were all qualitatively similar to responses seen in exercising humans. Thus, this study further supports the belief that the pig is a good model for studying the cardiopulmonary responses to exercise in humans.     

Design, goals and preliminary results of the first national breast cancer study--the Federal Ministry of Research and Technology study of "small breast cancer"

In the multicentre trial sponsored by the Federal Ministry for Research and Technology (= BMFT), mastectomy is compared with breast preservation in patients with pT1 NO MO breast cancer. On the basis of that protocol breast preservation can also be performed by smaller institutions thus implementing the health policy programme of effecting new treatment modalities on a broad basis. We can already recognise a substantial improvement in treatment standards applied by the different disciplines in the hospitals involved in the study. Special emphasis is placed on an optimal patient information about the possible treatment modalities involving the patients in the treatment decision. The evaluation of various prognostic factors will result in additional information on the biology of breast cancer. As a consequence, the definition of the group of patients suitable for breast preservation therapy can be clarified further.     

MR imaging of myositis ossificans: Variable patterns at different stages

Five patients with a palpable mass at presentation underwent magnetic resonance (MR) imaging. The final diagnosis was myositis ossificans (MO). MR imaging features, particularly after injection of gadopentetate dimeglumine, mimicked those of an inflammatory mass or neoplasm. The lesions were excised in three patients, and the Images were correlated with histologic findings. Three different appearances were noted on MR images, corresponding to the stages of maturation of MO. Two cases Involved early-stage lesions, and Tl-weighted MR images showed a mass with homogeneous intermediate signal intensity. Both lesions showed rim enhancement after contrast agent injection and high signal intensity on T2-weighted images. Pathologic specimens demonstrated stroma with masses of spindle cells in which osteoid production was interspersed. The enhanced rim of the lesion mimicked the expected MR appearance of an abscess or necrotic tumor. Areas of enhancement in adjacent muscle were also seen on postcontrast T1-weighted images. Intermediate-stage MO was present in one case; there was evidence of a thin rim of calcification on plain radiographs and fatty changes in the lesion on T1-weighted Images, corresponding with histologic findings. One case of a mature lesion showed a considerable degree of peripheral calcification both on MR images and at histology. MR imaging is nonspecific in the diagnosis of early-stage MO.     

A comparative study of reactive oxygen species in red muscle: pressure effects.

In ectotherms as well as in endotherms, the mitochondrial respiratory chain is the major source of reactive oxygen species (ROS) including the highly reactive, hydroxyl radical (OH*). It is known that the different steps involved in ROS production and the antioxidant systems are comparable in ectotherms and endotherms. But regulatory mechanisms in ROS production are less known especially in fish submitted to environmental changes. Firstly, we performed a ROS muscle metabolism interspecies study, using trout and eels as ectotherms and rats as endotherms, measuring OH* production, superoxide dismutase and catalase activities and in parallel oxygen consumption (MO2). Secondly, we studied the effects of an environmental factor (hydrostatic pressure) on ROS metabolism in both fish species. The results show that, at atmospheric pressure, fish have a higher OH*/MO2 ratio than rats which exhibit a higher superoxide dismutase activity. In fish exposed to hydrostatic pressure, this ratio is reversed so that for the same MO2 value, fish produce less OH* under hydrostatic pressure than at atmospheric pressure.     

MRI evaluation of microvascular obstruction in experimental reperfused acute myocardial infarction using a T1 and T2 preparation pulse sequence

PURPOSE: To investigate a T1 and T2 preparation pulse sequence to evaluate microvascular obstruction (MO) in a porcine model of reperfused acute myocardial infarction (AMI). MATERIALS AND METHODS: A total of 14 pigs with reperfused AMI underwent MRI examinations at baseline and three to four hours after reperfusion. MRI scans included a left ventricular functional study, T1 and T2 measurement on a 1.5T MRI system. At reperfusion, first-pass myocardial perfusion (FPMP) images were obtained after bolus injection of gadopentetate dimeglumine followed by an intravenous drip. Delayed contrast-enhanced MRI (DE-MRI) and T1 measurements were performed 30 and 45 minutes, respectively, after the bolus, during a constant infusion of gadopentetate dimeglumine. RESULTS: In 11 pigs MO was hypoenhanced in FPMP and DE-MRI. In later T1 preparation difference images postcontrast, MO was hyperenhanced while delayed hyperenhanced (DHE) regions appeared dark. MO areas on DE-MRI and T1 images were comparable. T1 reduction (%) postcontrast in MO was small compared to measurements from DHE regions (P < 0.0001) and similar to those from control segments (P = 0.66). Precontrast T1 and T2 values at reperfusion from MO and DHE regions were larger than in control regions. CONCLUSION: Using T1 preparation under a constant gadopentetate dimeglumine (Gd-DTPA) infusion, delayed imaging at 30 to 45 minutes demonstrates MO as a positive contrast with larger T1 values. Elevated T1 and T2 values in MO precontrast may also help to differentiate them from both control and DHE regions.     

Osteochondrom und multiple Osteochondrome

Purpose

Osteochondroma represents the most common form of benign bone tumor. Clinical manifestations include deformity of bone, compression of surrounding tissue and vascular or neurological compromise. Osteochondromas may be solitary (solitary osteochondroma, SO) or multiple (multiple osteochondromas MO). Recurrence after surgery is a known problem especially in MO and malignant transformation is rare but more common in MO than in solitary cases. Reliable recommendations regarding diagnostics and clinical follow-up are currently lacking.

Patients and methods

A comprehensive literature review and a review of own patient files with SO/MO treated between 2000 and 2011 in this hospital were performed. The age of patients at diagnosis, tumor localization, clinical aspects, recurrence and the risk of malignant transformation in secondary (i.e. epiexostotic) chondrosarcoma were analyzed. The follow-up including patients who received surgery ranged between 2 and 127 months for patients with SO and between 2 and 84 months for MO.

Results

A total of 39 patients with SO from this hospital were included in the study. Out of 36 patients who received surgery 3 recurrences were registered after an average time of 62 months. In addition, 11 patients with MO were identified and all received surgery. In 5 out of 11 cases recurrences occurred after an average time of 20.6 months. Secondary chondrosarcomas were not recorded in this series. According to the literature an increased risk of malignant transformation was found for osteochondromas of the axial skeleton, in the proximal aspect of the extremities, as well as for recurrent tumors and for MO. Pain and/or increase in size of lesions after skeletal maturation were the most common clinical signs of transformation. There was a wide time interval between the initial diagnosis and the development of secondary chondrosarcoma. In MO secondary chondrosarcoma has been described before skeletal maturity.

Conclusions

The risk of malignant transformation of SO is generally low. Axial lesions as well as recurrent osteochondromas and MO seem to have an increased risk of malignant transformation. The follow-up, requiring sufficient primary diagnostics, includes regular self-control and can usually be clinically carried out in more peripherally located lesions but in certain cases supplementary X-ray imaging is needed. In cases of anatomical regions which are more difficult to access manually, follow-up examination by magnetic resonance imaging (MRI) is the method of choice. Especially MO patients seem to benefit from long-term follow-up: when the tumor is located in the trunk and in (proximal) long bones MRI or whole-body MRI, respectively, should be performed once a year after skeletal maturity because of the higher risk of malignant transformation in these patients.     

Effectiveness of point-of-care oral ivabradine for cardiac computed tomography

BackgroundCoronary CT angiography (CCTA) is increasing seen as a first line investigation in patients with suspected coronary artery disease. Heart-rate control improves the image quality and diagnostic accuracy of CCTA. Typically, beta-blockers are administered to induce sinus bradycardia. Sinus bradycardia may also be induced by ivabradine. We hypothesized that in a real-world population ivabradine would be an effective alternative to metoprolol at heart rate lowering for CCTA.MethodsThis was a retrospective analysis of consecutive patients who were exposed to an ivabradine-based (IB) versus a metoprolol-only (MO) protocol to achieve a target heart rate </ = 65bpm. Hemodynamic responses to both strategies were compared along with differences in cost and the time expired from medication administration to CCTA.Results5955 consecutive patients were included in the analysis: 3211 were imaged during an era of a metoprolol only strategy (MO) and 2744 CCTA following an ivabradine based (IB) strategy. 2676 patients had heart rates >65 and received heart-rate lowering medication: 1958 patients had MO, and 718 received IB protocol. Target heart rate of </ = 65bpm was achieved in 77% of MO and 89% of IB patients (p < 0.01). The time from initial medication administration to CCTA was longer in the IB versus MO patients (77 versus 48 min, p < 0.01).ConclusionsIntroduction of a novel single dose ivabradine-based protocol to control heart rate for CCTA was more successful in achieving target heart rate than a metoprolol-only strategy. The use of ivabradine however incurred a 1.6-fold increase in the time delay from medication administration and imaging compared to a metoprolol only protocol.     

Gastric emptying after a new, more physiological anti-obesity operation: the Magenstrasse and Mill procedure

The Magenstrasse and Mill (M&;M) procedure for obesity is designed to preserve normal gastric emptying mechanisms. The hypothesis investigated in this study was that gastric emptying would be normal after the M&;M gastroplasty. Gastric emptying studies were performed using both liquid and solid test meals, in ten morbidly obese patients (MO group) and in 13 patients after the M&;M procedure (MM group). Seven people of normal weight served as controls and were matched for age, sex and height to the M&;M and MO groups. Three years after the M&;M procedure, mean (SD) weight loss was 42 (19) kg, with a mean loss of excess weight of 58% (20%). Gastric emptying half-times (t_1/2) are expressed in minutes, as median values (25th and 75th percentiles). The t_1/2 for solids was 97 (85-110) min in the control group, 140 (86-220) min in the MO group and 79 (46-150) min in the MM group. Median gastric emptying for solids was 0.7% (0.6%-0.8%) per minute in the control group, 0.5% (0.3%-0.8%) in the MO group and 0.9% (0.4%-1.4%) in the M&;M group. There were no statistically significant differences in the emptying times of the three groups. It is concluded that the M&;M procedure achieves acceptable weight loss, while preserving gastric emptying mechanisms and thus minimising possible side-effects such as vomiting, dumping and diarrhoea, which are common complications of gastric bypass procedures.     

良恶性石骨症的临床及X线分析

目的：探讨良、恶性石骨症的临床及X线平片的特征性表现,提高对本病的鉴别诊断水平。方法：对12例良恶性石骨症患者的临床资料及X线平片表现进行回顾性分析,其中良性5例,恶性7例。结果：良性病变的临床特点为早期无症状,发病轻,进展慢。恶性型临床特点为发病早,进展快,进行性贫血,血小板减少,肝脾及淋巴结肿大。实验室检查主要指标...     

Gastric emptying after a new, more physiological anti-obesity operation: the Magenstrasse and Mill procedure

The Magenstrasse and Mill (M&M) procedure for obesity is designed to preserve normal gastric emptying mechanisms. The hypothesis investigated in this study was that gastric emptying would be normal after the M&M gastroplasty. Gastric emptying studies were performed using both liquid and solid test meals, in ten morbidly obese patients (MO group) and in 13 patients after the M&M procedure (MM group). Seven people of normal weight served as controls and were matched for age, sex and height to the M&M and MO groups. Three years after the M&M procedure, mean (SD) weight loss was 42 (19) kg, with a mean loss of excess weight of 58% (20%). Gastric emptying half-times (t 1/2) are expressed in minutes, as median values (25th and 75th percentiles). The t 1/2 for solids was 97 (85-110) min in the control group, 140 (86-220) min in the MO group and 79 (46-150) min in the MM group. Median gastric emptying for solids was 0.7% (0.6%-0.8%) per minute in the control group, 0.5% (0.3%-0.8%) in the MO group and 0.9% (0.4%-1.4%) in the M&M group. There were no statistically significant differences in the emptying times of the three groups. It is concluded that the M&M procedure achieves acceptable weight loss, while preserving gastric emptying mechanisms and thus minimising possible side-effects such as vomiting, dumping and diarrhoea, which are common complications of gastric bypass procedures.