Novel lead molecule optimization targeting nicotinic receptor subtypes

针对烟碱受体亚型的新型先导分子优化

• 批准号: 7781228
• 负责人: Chenglong Li
• 金额: $ 22.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781228
• 关键词: Adrenergic Receptor; Agonist; Allosteric Site; Alzheimer' s Disease; Area; Attention deficit hyperactivity disorder; Autistic Disorder; Binding; Binding Sites; Biological; Biological Assay; Cessation of life; Charge; Cholinergic Agonists; Cigar; Cigarette; Classification; Clinical Trials; Computer Assisted; Computer Simulation; Coupled; Development; Disease; Drug Approval; Drug Delivery Systems; Drug Design; Epilepsy; Evaluation; Experimental Designs; Gilles de la Tourette syndrome; Goals; Hand; Human; Laboratories; Lead; Libraries; Ligands; Link; Mediating; Medical; Methods; Modeling; Molecular; Muscarine; Neurons; Nicotine; Nicotinic Receptors; Oral Tobacco; Parkinson Disease; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Play; Population; Process; Resources; Role; Schizophrenia; Screening procedure; Site; Structure; Time; United States; Work; base; cost; drug discovery; flexibility; improved; infancy; interest; molecular dynamics; nervous system disorder; new therapeutic target; novel; novel strategies; premature; programs; public health relevance; receptor; small molecule; success; virtual

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.

描述（由申请人提供）：该R21申请的重点是通过结构指导、计算机辅助合成药物化学方法优化新型先导分子。我们的目标是神经元烟碱乙酰胆碱受体（nAChR）。基于结构的药物设计作为一种“理性”的方法已经相当成功，促成了约50种化合物进入临床试验和许多药物批准。nAChR及其许多亚型与许多神经系统疾病有关，例如精神分裂症、注意力缺陷多动障碍、阿尔茨海默病、图雷特综合征、帕金森病、自闭症和某些类型的癫痫。此外，尼古丁是美国使用最多的成瘾性药物之一。考虑到1）其生理/病理生理重要性，2）时间和精力（和资源）致力于药物发现在这一领域在过去的二十年中，3）大多数药物发现计划在这一领域的目标正构位点[内源性激动剂（乙酰胆碱）结合位点]，以及4）很少有选择性靶向nAChR的特定亚型的药物被鉴定，需要寻求nAChR药物发现领域的新方法。在过去的几年里，我们的实验室已经研究了一类新的分子，作为负变构调节剂。使用计算的方法，我们最近确定了一个新的网站nAChR这些分子可能结合。最近，我们已经确定了一种新的先导分子，选择性抑制42 nAChR。这一发现的重要性在于，该分子是通过分子动力学模拟和虚拟筛选使用我们的计算模型的人类42 nAChR上的变构位点来鉴定的，从而验证了我们的模型并支持我们提出的方法。我们的假设是，这些变构位点的nAChRs的特定亚型的分子表征和计算建模将导致发现的分子，靶向特定亚型的nAChRs。我们的论点是，更大的结构多样性存在于变构网站比在orthosteric网站，一旦这些网站被确定和特点，nAChR亚型选择剂的发展将遵循。作为概念的证明，该R21提案集中于人42 nAChR上的负变构结合位点和选择性结合该位点的药物（负变构调节剂，NAM）的发现。我们的目标是1）表征人类42 nAChR上的变构结合位点，2）通过组合计算和合成药物化学方法提高我们的先导分子的效力和选择性。成功将被定义为a）对42个nAChR的选择性为1000倍，和B）效力增加100至1000倍。 公共卫生关系：历史上，通过使用改变由这些受体介导的功能过程的特定药物来鉴定受体。从亨利戴尔爵士对毒蕈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分类，药理学鉴定是标准。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，分子生物学方法已经鉴定出许多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，新受体亚型的剪切数已经扩展了受体特异性药物的可用性。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、注意缺陷多动障碍、阿尔茨海默病、图雷特综合征、帕金森病、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成瘾性最强的药物之一;据估计，7000万12岁及以上的人（占美国人口的29%）使用香烟，雪茄和/或咀嚼烟草产品，每年导致约440，000人过早死亡，每年直接医疗费用超过750亿美元。考虑到这些受体的重要性以及考虑到在过去二十年中用于发现选择性分子的时间和精力（和资源），已经鉴定出很少靶向烟碱受体的特定亚型的药物。需要寻求烟碱受体药物发现领域的新方法。我们的新靶点（我们实验室最近确定的变构位点），我们有前途的先导分子（最近通过虚拟筛选确定），以及我们合理的药物设计方法（涉及计算机辅助药物设计），为发现选择性靶向特定亚型烟碱受体的分子提供了一种有前途的方法。