Novel lead molecule optimization targeting nicotinic receptor subtypes

描述(由申请人提供)：本R21申请的重点是通过结构引导的、计算机辅助的合成药物化学方法进行新的铅分子优化。我们的靶标是神经元烟碱型乙酰胆碱受体(NAChR)。基于结构的药物设计作为一种“合理”的方法已经相当成功，为将~50种化合物引入临床试验和许多药物批准做出了贡献。NAChRs及其许多亚型与许多神经系统疾病有关，如精神分裂症、注意力缺陷多动障碍、阿尔茨海默病、抽动症、帕金森氏症、自闭症和某些类型的癫痫。此外，尼古丁是美国使用最频繁的成瘾药物之一。考虑到它们在生理学/病理生理学上的重要性，2)过去20年来在这一领域的药物发现所花费的时间和精力(和资源)，3)这一领域的大多数药物发现计划针对的是邻位位[内源性激动剂(乙酰胆碱)结合位点]，以及4)很少有选择性地针对特定亚型nAChRs的药物被确定，因此需要在nAChR药物发现领域寻求新的方法。在过去的几年里，我们的实验室研究了一类作为负变构调节剂的新型分子。利用计算方法，我们最近在nAChR上发现了一个新的位置，这些分子可能在那里结合。最近，我们发现了一种新的先导分子，它可以选择性地抑制42个nAChRs。这一发现的重要意义在于，通过分子动力学模拟和虚拟筛选，利用我们的计算模型对人类42nAChRs上的变构位点进行了鉴定，从而验证了我们的模型，并支持了我们提出的方法。我们的假设是，对特定亚型nAChRs上的这些变构位点进行分子表征和计算建模将导致发现针对特定亚型nAChRs的分子。我们的论点是，变构位点比正构位点存在更大的结构多样性，一旦这些位点被鉴定和表征，nAChR亚型选择剂的开发将随之而来。作为概念的证明，这项R21提案侧重于人类42个nAChRs上的负变构结合部位以及选择性结合该部位的药物的发现(负变构调节剂，NAMS)。我们的目标是1)表征人类42个nAChRs上的变构结合位点，以及2)通过计算和合成药物化学相结合的方法来提高我们的铅分子的效力和选择性。成功将被定义为a)对42个1000倍的nAChRs的选择性，以及b)100-1000倍的效力增加。 公共卫生相关性：历史上，受体是通过使用特定的药物来识别的，这些药物改变了这些受体介导的功能过程。从亨利·戴尔爵士对毒扁豆碱和尼古丁的研究到R.P.阿尔奎斯特对肾上腺素能受体的细分，药理学鉴定是常态。这些方法导致1)发现特定受体的生理重要性，2)识别新的治疗靶点，3)治疗疾病的新策略。在过去的25到30年里，分子生物学方法现在已经确定了一系列新的受体和新的受体亚型。由于这些方法与受体特异性药物无关，新受体亚型的剪切量已经超出了受体特异性药物的可获得性。尼古丁受体及其许多亚型与许多神经系统疾病有关，如精神分裂症、注意力缺陷多动障碍、阿尔茨海默病、抽动症、帕金森氏症、自闭症和某些类型的癫痫。此外，尼古丁是美国使用最频繁和最容易上瘾的毒品之一；据估计，12岁及以上的人(或美国人口的29%)使用香烟、雪茄和/或咀嚼烟草产品，每年导致约44万人过早死亡，每年的直接医疗费用超过750亿美元。考虑到这些受体的重要性，并考虑到过去20年来致力于发现选择性分子的时间和精力(和资源)，几乎没有针对特定亚型尼古丁受体的药物被识别出来。需要在尼古丁受体药物发现领域寻求新的方法。我们的新靶点(我们实验室最近发现的一个变构位点)，我们有希望的先导分子(最近通过虚拟筛选确定)，以及我们的合理药物设计方法(包括计算机辅助药物设计)，为发现选择性靶向特定亚型尼古丁受体的分子提供了一种有希望的方法。

DESCRIPTION (provided by applicant): The focus of this R21 application is novel lead molecule optimization through structure-guided, computer-aided synthetic medicinal chemistry approaches. Our target is the neuronal nicotinic acetylcholine receptor (nAChR). Structure-based drug design as a "rational" method has been quite successful, contributing to the introduction of ~50 compounds into clinical trials and to numerous drug approvals. nAChRs and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition nicotine is one of the most heavily used addictive drugs in the United States. Considering 1) their physisological/pathophysiological importance, 2) the time and effort (and resources) devoted to drug discovery in this area over the past twenty years, 3) most drug discovery programs in this area targeting orthosteric sites [endogenous agonist (acetylcholine) binding sites], and 4) few drugs that are selectively targeting specific subtypes of nAChRs being identified, new approaches in the area of nAChR drug discovery need to be pursued. For the past several years our laboratories have investigated a novel class of molecules that act as negative allosteric modulators. Using computational approaches we have recently identified a novel site on nAChR where these molecules likely bind. Most recently we have identified a novel lead molecule that selectively inhibits 42 nAChRs. The importance of this discovery is that this molecule was identified via molecular dynamics simulation and virtual screening using our computational model of the allosteric site on human 42 nAChRs, thus validating our model and supporting our proposed approaches. Our hypothesis is that molecular characterization and computational modeling of these allosteric sites on specific subtypes of nAChRs will lead to the discovery of molecules that target specific subtypes of nAChRs. Our contention is that greater structural diversity exists in allosteric sites than in orthosteric sites and, once these sites are identified and characterized, the development of nAChR subtype-selective agents will follow. As proof of concept, this R21 proposal focuses on a negative allosteric binding site on human 42 nAChRs and the discovery of drugs that selectively bind this site (negative allosteric modulators, NAMs). Our goals are 1) to characterize the allosteric binding sites on human 42 nAChRs and 2) to improve the potency and selectivity of our lead molecule through combined computational and synthetic medicinal chemistry approaches. Success will be defined as a) selectivity toward 42 nAChRs of 1000 fold, and b) a 100- to 1000-fold increase in potency. PUBLIC HEALTH RELEVANCE: Historically, receptors were identified through the use of specific drugs that altered functional processes mediated by these receptors. From Sir Henry Dale's work with muscarine and nicotine to R.P. Ahlquist's sub- classification of adrenergic receptors, pharmacological identification was the norm. These approaches led 1) to the discovery of the physiological importance of specific receptors, 2) to the identification of new therapeutic targets, and 3) to novel strategies that treat disease. Over the past 25 to 30 years, molecular biological approaches have now identified a host of new receptors and new receptor subtypes. Since these approaches are not linked to receptor-specific drugs, the shear numbers of new receptor subtypes have outstretched the availability of receptor-specific drugs. Nicotinic receptors and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition, nicotine is one of the most heavily used and addictive drugs in the United States; it is estimated that 70 million people 12 and older (or 29 percent of the U.S. population) use cigarettes, cigars and or chewing tobacco products, resulting in ~ 440,000 premature deaths each year with an annual cost of more than $75 billion in direct medical charges. Taking into consideration the importance of these receptors as well as considering the time and effort (and resources) devoted to the discovery of selective molecules over the past twenty years, few drugs that target specific subtypes of nicotinic receptors have been identified. New approaches in the area of nicotinic receptor drug discovery need to be pursued. Our novel target (an allosteric site recently identified by our laboratory), our promising lead molecule (recently identified via virtual screening), and our rational drug design approach (involving computer-aided drug design), provide a promising approach for the discovery of molecules that selectively target specific subtypes of nicotinic receptors.