Nicotinic Ligand Development to Target Smoking Cessation and Gain a Molecular Level Understanding of Partial Agonism

以戒烟为目标的烟碱配体开发并获得对部分激动的分子水平理解

• 批准号: EP/N024117/1
• 负责人: Timothy Gallagher
• 金额: $ 92.32万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FN024117%2F1
• 关键词: Nicotinic; Ligand; Development; Target; Smoking

This proposal addresses the mechanism of action of a new class of "drug" used for smoking cessation based on agents which bind to and partially activate the high affinity nicotine receptors in the brain.The "first to market" drug (varenicline) is a nicotinic partial agonist but is subject to FDA restrictions that reflect an inadequate level of receptor subtypes selectivity; varenicline targets the high affinity nicotinic binding site (alpha4beta2) but is also a full agonist at the alpha7 receptor. If poor subtype selectivity is responsible for varenicline's side effects, a better insight into how ligand structure links to the receptor (and subtype) function is key, but to do this we will need to broaden our appreciation the modes of ligand binding. Cytisine, which is our focus, is a naturally-occurring partial nicotinic agonist that has been used for smoking cessation, and so itself is also of commercial potential. We have recently developed robust and efficient chemistry that allows us to modify cytisine directly, specifically, and at an otherwise almost unexplored site on the molecule. This chemistry uses cytisine as a very accessible starting point to explore a range of new structural variants to probe novel binding modes and so potentially new ways to achieve nicotinic subtype specificity. Recent speculation as to those molecular features of cytisine (and varenicline) that mediate ligand binding to nicotinic receptors will be investigated by (i) making specific molecules whose structural features will attenuate ligand binding and by (ii) expanding the range of ligand-protein contacts made in a very directed manner. We will build on preliminary structural and computational studies and create new ligands associated with C3 and C4 positions of cytisine. Both classes, but especially C4 variants, offer an opportunity to engage existing (but currently "spectator") protein residues in ligand binding that are within that region of the binding site directly associated with differentiation between the key receptor subtypes. Modifying existing binding by accessing these additional modes will allow us to rationally "tune" subtype selectivity. Success will dramatically improve our view of structure-relationships within nicotinic ligands and offer insights to medicinal chemists as to the range and spatial distribution of an enhanced "active site" template.We will study the specific detail of these new interactions using crystallography to pinpoint the ligand within a model protein and so identify newly "engaged" residues. We will then link this to the full human receptor protein, which still cannot be crystallised, in order to understand how ligand binding, as well as any new modes of binding, translates into how the full protein receptor functions. We will do this with new and powerful computational methods to look at the detail of the consequences of ligand binding in order to correlate ligand structure to whole receptor function.We have a series of collaborators in place in what is already a multidisciplinary programme to enable us to explore the biological, structural properties and commercial potential of these new ligands, and to correlate that to our predictive and analytical computational methods. Success in this project will critically depend on a close interplay between our new computational techniques and the synthetic chemistry. We will shed light on molecular level features of ligand structure which determine subtype selectivity and this will have longer term implications for safety/user acceptability within smoking cessation agents. By understanding the detail of how ligand structure links to overall receptor function, and this is an especially challenging computational task, we hope to separate subtype selectivity issues from more generic "downstream" effects (associated with nicotinic activation) which has the potential to guide further development of nicotinic-based therapeutic agents.

该提案探讨了一种新的“药物”的作用机理，用于戒烟，基于与大脑中的高亲和力尼古丁受体结合并激活的药物。“首先到市场”药物（varenicline）是一种烟碱局部偏剂，但受到FDA的限制，这反映了受体级别的不足级别的spectition spectionitive subseptivity subsepsivity subseptespesspeps suppetspespesspespyplestyplesivity; Varenicline靶向高亲和烟碱结合位点（alpha4beta2），但也是α7受体的完整激动剂。如果较差的亚型选择性负责Varenicline的副作用，那么对配体结构如何与受体（和亚型）函数链接的更好洞察力是关键，但是要做到这一点，我们将需要扩大我们的配体结合模式。 Cytisine是我们的重点，是一种天然疾病的烟碱激动剂，已用于戒烟，因此本身也具有商业潜力。我们最近开发了可靠，有效的化学性质，使我们能够直接（具体来说）并在分子上的几乎未开发的位点进行修饰。该化学方法使用cytisine作为一个非常可访问的起点，探索一系列新的结构变体来探测新型的结合模式，并因此具有实现烟碱类亚型特异性的潜在新方法。 （i）（i）制作特定的分子，其结构特征将减弱配体结合，以及（ii）扩大以非常有指导的方式，以（ii）扩大了以非常有指导的方式扩展的特定分子。我们将基于初步的结构和计算研究，并创建与Cytisine的C3和C4位置相关的新配体。这两个类别（尤其是C4）都提供了一个机会，可以使现有（但目前“观众”）蛋白质残基在配体结合中的现有蛋白质残基与与关键受体亚型之间的分化直接相关的结合位点内的该区域内。通过访问这些附加模式来修改现有绑定将使我们能够合理地“调整”亚型选择性。成功将极大地改善我们对烟碱配体中结构关系的看法，并就药物化学家提供有关增强的“活跃位点”模板的范围和空间分布的见解。我们将使用晶体学的这些新相互作用来研究这些新相互作用的细节，以在模型蛋白质中查明配体，从而确定新型的“新型”。然后，我们将将其与完全无法结晶的完整人体受体蛋白联系起来，以了解配体结合以及任何新的结合模式如何转化为完整蛋白受体的功能。我们将采用新的和强大的计算方法来研究配体结合的后果，以将配体结构与整个受体功能相关联。我们在已经是一个多学科的程序中拥有一系列的合作者，以使我们能够探索这些新物种的生物学，结构性，结构性和商业潜力，从而与我们的预测方法相关联和分析，并分析了这些方法。该项目的成功将在很大程度上取决于我们的新计算技术与合成化学之间的紧密相互作用。我们将阐明确定亚型选择性的配体结构的分子水平特征，这将对吸烟剂中的安全/用户的可接受性具有长期影响。通过了解配体结构如何与整体受体功能联系起来，这是一项特别具有挑战性的计算任务，我们希望将亚型选择性问题与更通用的“下游”效应（与烟碱激活相关）分开，这有可能指导基于烟碱的治疗剂的进一步发展。

项目成果

Entropy of Simulated Liquids Using Multiscale Cell Correlation.

• DOI: 10.3390/e21080750
• 发表时间: 2019-07-31
• 期刊: Entropy (Basel, Switzerland)
• 作者: Ali HS;Higham J;Henchman RH
• 通讯作者: Henchman RH

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

• DOI: 10.1021/acs.jctc.1c00547
• 发表时间: 2021-10-12
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Ansell TB;Curran L;Horrell MR;Pipatpolkai T;Letham SC;Song W;Siebold C;Stansfeld PJ;Sansom MSP;Corey RA
• 通讯作者: Corey RA

New methods: general discussion.

新方法：一般性讨论。

• DOI: 10.1039/c6fd90075e
• 发表时间: 2016
• 期刊: Faraday discussions
• 影响因子: 3.4
• 作者: Angulo G

Biomolecular Simulations in the Time of COVID19, and After.

• DOI: 10.1109/mcse.2020.3024155
• 发表时间: 2020-11
• 期刊: Computing in science & engineering
• 影响因子: 2.1
• 作者: Amaro RE;Mulholland AJ
• 通讯作者: Mulholland AJ