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博士後期課程
平成 28 年度
武蔵野大学大学院
薬科学研究科
薬科学専攻 博士後期課程
入学試験問題
［ 英語 ］
【問題１】次の文章を読んで各問に答えよ。
(a)Preclinical
strategies that are used to identify potential drug candidates include target-based screening, phenotypic
screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies
have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the
molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US
Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were
first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics.
The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule
drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches,
respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric
approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high
attrition rates and low productivity in pharmaceutical research and development.
（中略）
The molecular mechanism of action (MMOA) is defined here as the interaction between a drug and its target (or
targets) that creates a specific response. These specific molecular interactions link structure to function in such a
manner as to provide a therapeutically effective and safe response. In this context, the MMOA is differentiated from
mechanism of action (MOA), which describes the mechanism in the context of the physiological response — such as
antihistamines, anti-inflammatory, and so on.
There are many facets of this interaction that ultimately result in the desired therapeutic outcome. For example, the site
of interaction (allosteric or orthosteric), molecular descriptors of the binding interaction (such as affinity and binding
kinetics), the functional impact (for example, receptor agonism, modulation or antagonism) and the specificity of the
functional outcome (for example, activation of specific signalling pathways) all contribute to the MMOA and affect the
ultimate pharmacological response.
Conformational mechanisms
(b)For
conformational mechanisms, binding of the drug to the target involves a conformational change in the target that
couples drug binding to a response. For example, sirolimus binds to the peptidylprolyl isomerase FKBP12, which
stabilizes a conformation that subsequently inhibits the kinase activity of mammalian target of rapamycin.
Redox mechanisms
Redox is short for reduction–oxidation reactions in which the pharmacological response to the drug is a consequence
of electron transfer between the drug and a physiological target. For example, the antiprotozoal activity of nitazoxanide
(Alinia) is believed to be due in part to interference with the pyruvate–ferredoxin oxidoreductase enzyme-dependent
electron transfer reaction, which is essential to anaerobic energy metabolism.
facet 面，be short for ～の略で
（Swinney, D. C.; Anthony, J.
―How were new medicines discovered?‖ Nature Rev. Drug Discov. 2011, 10, 507 改）
（解答は日本語で可）
(1) MMOA と MOA の定義の違いを説明しなさい．
(2) 下線部 (a) を和訳しなさい．また，first-in-class な小分子医薬品の開発の主流がどのように変化してきて
いると分析されているか，簡単に説明しなさい．
(3) 下線部 (b) を和訳しなさい．
(4) Redox mechanisms に関する具体例を説明しなさい．
【問題２】次の文章を読んで各問に答えよ。
Most dementias occur more frequently as people age. As a result, in societies where life
expectancy has been considerably extended, these diseases are becoming a major public health concern.
（１）Approximately 15 percent of people who live to the age of 65 will develop some form of
dementia; by age 85, that proportion increases to at least 35 percent. Of all the dementias, Alzheimer's
disease is the most common. Four million Americans currently suffer from the condition, and experts
estimate that 22 million people around the world will be so afflicted by 2025. The foundation of today's
understanding of Alzheimer's was built by researchers who directly examined patients' brains.
Microscopic views have revealed a loss of nerve cells in certain regions of the brain, such as the
hippocampus, a center for memory, and the cerebral cortex, which is involved in reasoning, memory,
language and other important thought processes. The other directly observable hallmarks of Alzheimer's
disease are clusters of proteins in the brain. These accumulations occur in two forms: those found inside
nerve cells and those found between cells. The clusters in the interior are called neurofibrillary tangles,
and they resemble pairs of threads wound around each other in a helix. Analyses made it clear that these
tangles consist of a protein called tau. Tau is significant because it binds to a protein named tubulin,
which in turn forms structures known as microtubules. Unlike neurofibrillary tangles, deposits of
amyloid protein gather in the spaces between nerve cells. The nearby neurons often look swollen and
deformed, and the clusters of protein--sometimes called senile or amyloid plaques--are usually
accompanied by reactive inflammatory cells called microglia, which are part of the brain's immune
system and might be trying to degrade and remove damaged neurons or perhaps the plaques themselves.
Intensive efforts to isolate the ingredients of these plaques culminated in 1984 that a principal
component was a peptide--that is, a very short protein fragment--made up of either 40 or 42 amino acids.
This identification of what is now termed the beta-amyloid peptide was quickly followed by the
sequencing of the gene for the longer protein from which this peptide originates: the ß -amyloid
precursor protein (ßAPP). （George-Hyslop, Scientific American, 2000 より抜粋）、neurofibrillary
tangle：神経原繊維変化、senile plaque；老人斑
問1
下線部(1)を和訳せよ
問2
アルツハイマー病の病理的特徴を 3 つ挙げ、各々について説明せよ。