Commercial Software for Modeling of G Protein-Coupled Receptors

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.