Commercial Software for Modeling of G Protein-Coupled Receptors

描述(申请人提供)：G蛋白偶联受体(GPCRs)功能障碍会导致多种疾病，如阿尔茨海默氏症、帕金森氏症、糖尿病、侏儒症、色盲、视网膜色素变性和哮喘。GPCRs还与抑郁症、精神分裂症、失眠、高血压、阳萎、焦虑、压力、肾功能衰竭、几种心血管疾病和炎症有关。不幸的是，只有为数不多的GPCR晶体结构在公共领域可用。因此，为了采用基于结构的方法来设计针对GPCRs的药物，迫切需要开发能够导致生产准确的GPCRs模型的技术。构建准确的GPCR模型的一个重要部分是对脂质双层膜的适当处理。我们建议开发一个新的商业软件包，能够对粗颗粒脂双层/水环境中的全原子GPCR模型进行长时间尺度和长时间尺度的分子动力学模拟。最近引入的一种多尺度方法已经在探索性研究中得到验证，该方法使用简化的、计算高效的脂双层和水的粗粒度表示，并结合蛋白质的原子模型。这种混合的AA-CG方法将被合并到一个强大的、用户友好的商业软件包中，该软件包面向专注于开发针对A类GPCRs的药物的制药和生物技术研究人员。 与公众健康相关：G蛋白偶联受体(GPCRs)是新药开发中最重要的靶蛋白家族之一；目前市场上批准的所有药物中约有50%-60%针对GPCRs，几乎所有的制药公司都在积极研究GPCRs。GPCRs与阿尔茨海默氏症、帕金森氏症、糖尿病、侏儒症、色盲、视网膜色素变性、哮喘、抑郁症、精神分裂症、失眠、高血压、阳萎、焦虑、压力、肾功能衰竭、心血管疾病和炎症有关。我们建议开发易于使用的商业软件，旨在为GPCRs产生准确的模型，这些模型可以用于针对这一重要的蛋白质超家族的新药的设计。

DESCRIPTION (provided by applicant): Dysfunction of G protein-coupled receptors (GPCRs) results in diseases as diverse as Alzheimer's, Parkinson's, diabetes, dwarfism, color blindness, retina pigmentosa and asthma. GPCRs are also involved in depression, schizophrenia, sleeplessness, hypertension, impotence, anxiety, stress, renal failure, several cardiovascular disorders and inflammations. Unfortunately, only a handful of GPCR crystal structures are available in the public domain. Therefore, in order to employ structure-based approaches to the design of drugs that target GPCRs, there is a critical need to develop technology that can lead to the production of accurate models of GPCRs. An essential part of constructing accurate GPCR models is the proper treatment of the lipid bilayer membrane. We propose to develop a novel commercial software package capable of performing long length-scale and time-scale molecular dynamics simulations of all-atom GPCR models in coarse grain lipid bilayer/water environments. A recently introduced multi-scale methodology using simplified and computationally efficient coarse-grain representations of lipid bilayers and water in combination with atomistic models for proteins has been validated in exploratory studies. This mixed AA-CG methodology will be incorporated into a powerful, user-friendly commercial software package directed at pharmaceutical and biotechnology researchers focusing on development of drugs that target class A GPCRs. PUBLIC HEALTH RELEVANCE: G protein-coupled receptors (GPCRs) are one of the most important families of target proteins for the development of new medicines; approximately 50-60% of all approved drugs on the market today target GPCRs and nearly all pharmaceutical companies are actively investigating GPCRs. GPCRs are involved in Alzheimer's, Parkinson's, diabetes, dwarfism, color blindness, retina pigmentosa, asthma, depression, schizophrenia, sleeplessness, hypertension, impotence, anxiety, stress, renal failure, cardiovascular disorders, and inflammations. We propose to develop easy-to-use commercial software aimed at producing accurate models for GPCRs that can be used in the design of new medicines that target this important superfamily of proteins.