Using reverse docking for target identification and its applications for drug discovery

ABSTRACT

Introduction: In contrast to traditional molecular docking, inverse or reverse docking is used for identifying receptors for a given ligand among a large number of receptors. Reverse docking can be used to discover new targets for existing drugs and natural compounds, explain polypharmacology and the molecular mechanism of a substance, find alternative indications of drugs through drug repositioning, and detecting adverse drug reactions and drug toxicity.

Areas covered: In this review, the authors examine how reverse docking methods have evolved over the past fifteen years and how they have been used for target identification and related applications for drug discovery. They discuss various aspects of target databases, reverse docking tools and servers.

Expert opinion: There are several issues related to reverse docking methods such as target structure dataset construction, computational efficiency, how to include receptor flexibility, and most importantly, how to properly normalize the docking scores. In order for reverse docking to become a truly useful tool for the drug discovery, these issues need to be adequately resolved.     

Statistical Approaches in the Analysis of Gene Expression Data Derived from Bone Regeneration Specific cDNA Microarrays

Abstract

Recent advances in molecular biology (e.g., cDNA microarray technology) enables the simultaneous monitoring of the expression level of thousands of genes. Due to the massive amount of complex data generated, sophisticated statistical approaches are necessary in order to properly address the experimental investigation. In this paper, we present statistical analysis of cDNA microarray data derived from bone regeneration experiments. Several interesting features from these data distinguish it from commonly used microarray experiment (i.e., separate hybridization of mRNA samples from reference and experimental tissues, selectively spotted cDNA sequences and 1060 systematically selected blank spots included in each array). Using this data set, we propose new methods for bioinformatic data normalization, as well as the modification and application of various other published methods in order to identify co-regulated gene expression patterns during the healing of a bone fracture. The proposed normalization methods perform effectively to eliminate the variations with a simple algorithm. Results from our cluster analysis revealed several clusters having distinct gene expression patterns during fracture healing. Our simulation study supports the reliability of the proposed methods.     

An extended version of the theory of planned behavour: Prediction of intentions to quit smoking using past behaviour as moderator

It was hypothesised that: (i) intentions to quit smoking were predictable from group identity, self-identity, moral norms and past quit attempts, beyond the components of the Theory of Planned Behaviour (TPB), and (ii) that past experiences with the behaviour (quit attempts) would increase the predictive utility of the extended TPB model on intentions. The data was collected among 357 daily smoking students (M = 24 years). The TPB components accounted for 12.3% of the variance in quitting intentions, while the extension variables added 16.5% to the explained variance in intentions beyond the impact of the TPB. Past behaviour had the strongest impact on intentions (α = 0.30), followed by moral norms (α = 0.25), perceived behavioural control (PBC, α = 0.20), attitude (α = 0.18) and group commitment (α = ?0.11). By splitting the sample into three categories of past quit attempts the picture changed, revealing that the predictive utility of the TPB increased with the number of quit attempts (no past quit attempt, R² = 1%, ns and several past quit attempts, R² = 12.3%, p < 0.001). Moreover, PBC and group commitment were significantly stronger predictors of intention among those who had several previous quit attempts compared with those who never had tried to quit smoking. The extended TPB model explained 1% and 28% of the variance in intentions among those with no and several previous quit attempts, respectively. The practical implications of these results for the development of interventions to encourage smokers to quit smoking are outlined.     

丁香油质量标准的研究

目的：起草药用辅料丁香油的质量控制标准。方法：比较国内外丁香油质量标准,主要对其薄层鉴别和含量测定方法进行增修订。结果：建立的丁香油和丁香茎叶油质量标准已收载于2015年版《中国药典》。结论：本研究起草的丁香油质量标准,符合中国国情现状,能有效地控制药用辅料丁香油的质量。     

LC-MS/MS法鉴定注射用多西他赛中的有关物质

采用LC-MS/MS法对注射用多西他赛中的有关物质进行鉴定。采用乙酸乙酯提取注射剂,以去除制剂中影响LC-MS/MS离子化效果的磺丁基-β-环糊精等辅料,然后对提取物中的有关物质进行LC-MS/MS鉴定。采用LC-ESI-MS/MS测定各有关物质的一级和二级质谱图,并对准分子离子的各个产物离子进行归属,对各杂质可能的结构进行推测。在所建立的条件下,多西他赛及其有关物质分离良好,共鉴定了注射用多西他赛中的9个有关物质结构,其中4个有关物质为首次在注射用多西他赛中发现。本文所建立的LC-MS/MS法可以有效地分离分析多西他赛及其有关物质,为其制剂的质量控制和工艺优化提供参考。     

金疮小草化学成分的分离与鉴定

目的对金疮小草的化学成分进行研究。方法采用硅胶吸附柱色谱、ODS柱色谱、制备薄层色谱和半制备型高效液相色谱分离纯化,根据1H-NMR、13C-NMR等谱学数据进行结构鉴定。结果从金疮小草干燥全草的甲醇提取物的乙酸乙酯萃取物中分离得到15个单体化合物,分别鉴定为ajugacumbin A(1)、ajugacumbin B(2)、ajuganipponin B(3)、ajugamarin F4(4)、ajugarin I(5)、ajugamarin A1(6)、ajugamarin A1 chlorhydrin(7)、芹菜素(apigenin,8)、木犀草素(luteolin,9)、金合欢素(acacetin,10)、咖啡酸甲酯(methyl caffeate,11)、4-hydroxy-4-(3-oxo-1-butenyl)-3,5,5-trimethylcyclohex-2-en-1-one(12)、香草酸(vanillic acid,13)、黑麦草内酯(loliolide,14)和(10E,15Z)-9,12,13-trihydroxyoctadeca-10,15-dienoic acid(15)。结论其中化合物11和12为首次从筋骨草属中分离得到,化合物7和15为首次从金疮小草中分离得到。     

Identification of non‐reported bupropion metabolites in human plasma

Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non‐reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non‐reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC–MS/MS at 0, 6 and 24 h. Two non‐reported metabolites (M1 and M3) were identified with mass‐to‐charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4–M7). These new metabolites may provide new insight and broaden the understanding of bupropion's variability in clinical pharmacokinetics. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd.     

苦石莲化学成分的分离与鉴定（IV）

目的对苦石莲中的化学成分做进一步研究。方法采用硅胶柱色谱、凝胶柱色谱和重结晶等多种方法分离纯化,根据理化性质及波谱学数据进行结构鉴定。结果分离得到9个化合物,分别鉴定为全反式-5-脱氧戊糖酸-γ-内酯(all-trans-5-deoxy-pentonic acid-γ-lactone,1)、腺苷(adeno-sine,2)、胡萝卜苷-6’-O-硬脂酸酯(daucosterol-6’-O-stearate,3)、7-acetoxybonducellpin C(4)、caesal-pinin K(5)、norcaesalpinin E(6)、neocaesalpin A(7)、neocaesalpin L(8)、neocaesalpin M(9)。结论化合物1、2为首次从云实属植物中分离得到,化合物3～5、7为首次从喙荚云实植物中分离得到。     

蚊子草化学成分的研究（Ⅱ）

目的 研究蚊子草[Filipendula palmate (Pall) Maxim]的化学成分。方法 采用多种柱色谱技术进行分离纯化,根据化合物的理化性质和波谱数据鉴定结构。结果 分离鉴定了 6 个已知化合物,分别是芹菜素（1）、山柰酚（2）、山柰酚-3-O-α-L-呋喃阿拉伯糖苷（3）、山柰酚-3-O-α-L-吡喃鼠李糖苷（4）、β-谷甾醇（5）和胡萝卜苷（6）。结论 化合物 5、6 为首次从该植物中分离得到,化合物 1~4 为首次从该属植物中分离得到。     

Oleamide restores sleep in adult rats that were subjected to maternal separation

Maternal separation (MS) induces a series of changes in rats' behavior; among them a reduction in spontaneous sleep. One potentially impaired system is the endocannabinoid system (eCBs), since it contributes to generate sleep. To investigate if there are situations early in life that affect the eCBs, which would contribute to make rats vulnerable to suffering insomnia, we studied the rodent model of MS. Rats were separated from their mothers for 3 h-periods daily, from postnatal day (PND) 2 to PND 16. Once they gained 250 g of body weight (adult rats), they were implanted with electrodes to record the sleep-waking cycle (SWC). MS rats and non-MS (NMS) siblings were assigned to one of the following groups: vehicle, oleamide (OLE, an agonist of the cannabinoid receptor 1, CB1R), OLE + AM251 (an antagonist of the CB1R) and AM251 alone. Expression of the CBR1 receptor was also analyzed in the frontal cortex (FCx) and in the hippocampus (HIP) of both NMS and MS rats. Results indicated that MS induced a reduction in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep with the consequent increase in waking (W) as compared to NMS siblings. OLE normalized the SWC, and AM251 blocked such an effect. CB1R expression was reduced in the FCx and in the HIP of MS rats. Our results indicate that MS reduces sleep and CB1R expression and OLE improves sleep in adult rats.