Commercial Software for Modeling of G Protein-Coupled Receptors

描述（由申请人提供）：G蛋白偶联受体（GPCR）功能障碍导致多种疾病，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。GPCR还涉及抑郁症、精神分裂症、失眠、高血压、阳痿、焦虑、压力、肾衰竭、几种心血管疾病和炎症。不幸的是，只有少数的气相化学还原晶体结构是在公共领域。因此，为了采用基于结构的方法来设计靶向GPCR的药物，迫切需要开发能够产生GPCR的精确模型的技术。构建准确的GPCR模型的一个重要部分是适当处理脂质双层膜。我们建议开发一种新的商业软件包，能够进行长的长度尺度和时间尺度的分子动力学模拟的全原子GPCR模型在粗粒脂质双层/水的环境。最近推出的多尺度方法，使用简化的和计算效率高的粗粒表示的脂质双层和水结合蛋白质的原子模型已在探索性研究中得到验证。这种混合AA-CG方法将被纳入一个强大的，用户友好的商业软件包，针对制药和生物技术研究人员专注于开发药物的目标A类GPCR。 公共卫生相关性：G蛋白偶联受体（GPCR）是新药开发中最重要的靶蛋白家族之一;目前市场上所有批准的药物中约有50-60%以GPCR为靶点，几乎所有制药公司都在积极研究GPCR。GPCR涉及阿尔茨海默氏症、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、阳痿、焦虑、应激、肾衰竭、心血管疾病和炎症。我们建议开发易于使用的商业软件，旨在为GPCR生成准确的模型，这些模型可用于设计针对这一重要蛋白质超家族的新药。

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.