BACKGROUND & AIMS:
:Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier. The decline of drug discovery output in the last decades, quite obvious in neuropharmacology, coincided with the advent of the single target-focused search of potent ligands selective for a well-defined protein, deemed critical in a given pathology. However, all the widespread neuro-psychic troubles are multi-mechanistic and polygenic, their complex etiology making unsuited the single-target drug discovery. An evolving approach, based on systems biology considers that a disease expresses a disturbance of the network of interactions underlying organismic functions, rather than alteration of single molecular components. Accordingly, systems pharmacology seeks to restore a disturbed network via multi-targeted drugs. This review notices that neuropharmacology in fact relies on drugs which are multi-target, this feature having occurred just because those drugs were selected by phenotypic screening in vivo, or emerged from serendipitous clinical observations. The novel systems pharmacology aims, however, to devise ab initio multi-target drugs that will appropriately act on multiple molecular entities. Though this is a task much more complex than the single-target strategy, major informatics resources and computational tools for the systemic approach of drug discovery are already set forth and their rapid progress forecasts promising outcomes for neuropharmacology.
背景与目标:
:Neuropharmacology在过去取得了几项重大成就,但最近几十年来在脑部疾病的药物治疗方面并未取得任何飞跃。而且,目前用于神经病学和精神病学的药物减轻了症状,同时几乎不能治愈任何疾病原因,这主要是因为大多数神经精神病学综合征的病因学知之甚少。这篇评论认为,这在很大程度上是由于分析还原论方法在神经科学中的不平衡流行所致,其集中在细胞和分子水平上,而对整合的大脑活动的理解仍然更加薄弱。在过去的几十年中,在神经药理学领域,药物发现产量的下降非常明显,这与对一种确定的蛋白质有选择性的有效配体的单一靶标集中搜索的出现相吻合,这被认为在给定的病理学中至关重要。但是,所有广泛存在的神经心理问题都是多机制的和多基因的,其复杂的病因使其不适用于单靶标药物的发现。一种基于系统生物学的不断发展的方法认为,疾病是对生物功能基础相互作用网络的一种干扰,而不是单个分子成分的改变。因此,系统药理学试图通过多靶点药物恢复受干扰的网络。该评论注意到神经药理学实际上依赖于多靶点药物,出现这种特征仅仅是因为这些药物是通过体内表型筛选选择的,或者是从偶然的临床观察中出现的。然而,该新颖的系统药理学旨在设计从头开始的多靶标药物,其将适当地作用于多个分子实体。尽管这是一项比单目标策略复杂得多的任务,但已经为药物发现的系统方法提出了主要的信息学资源和计算工具,并且它们的快速进展预示了神经药理学的前景。