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Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics

药物结合位点静电的全激酶组光谱研究

基本信息

批准号：
8973668
负责人：
Nicholas Mark Levinson
金额：
$ 24.82万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-13 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8973668
关键词：
Address Affect Benchmarking Binding Binding Sites Biological Assay Cancer Etiology Cause of Death Cell Proliferation Chemical Structure Chemicals Chronic Myeloid Leukemia Clinic Comparative Study Complex Cytotoxic agent Data Set Development Disease Drug Binding Site Drug Industry Effectiveness Electrostatics Environment Fluorescence Fluorescence Spectroscopy Fluorescent Probes Goals Growth Human Hydrogen Bonding Location Malignant Neoplasms Malignant neoplasm of lung Maps Measurement Measures Mentors Methods Molecular Target Mutate Mutation Pathology Patients Pharmaceutical Preparations Phase Phosphotransferases Physical Chemistry Physical environment Play Property Protein Family Protein Kinase Protein Kinase Inhibitors Proteins Radiation therapy Radiosurgery Reporting Research Role Series Signal Pathway Site Spectrum Analysis Structure Techniques Testing Time Translating Variant Water Work abstracting analog base cancer type chemical group design electric field experience inhibitor/antagonist insight kinase inhibitor member molecular dynamics physical property protein kinase inhibitor research study scaffold small molecule spectroscopic survey success tumorigenesis

项目摘要

Project Summary / Abstract Protein kinases play central roles in the signaling pathways that regulate the growth and proliferation of cells, and aberrant kinase activity contributes to the development of many cancers. Recent success in treating particular cancers with targeted protein kinases inhibitors, notably lung cancer and chronic myeloid leukemia, underscores the importance of these proteins in oncogenesis, and highlights the need for additional kinase inhibitors to treat other cancers. The development of new kinase inhibitors is challenging because the high sequence conservation of the kinase ATP-binding site, the major site targeted by these small molecules, makes it difficult to obtain compounds that are selective for particular kinases. The current study aims to address this problem through an entirely new experimental approach that utilizes advances in physical chemistry. In Aim 1, a new spectroscopic technique called vibrational Stark spectroscopy will be used to construct a map of the electrostatics of the ATP-binding site and how it varies across the ~500 members of this protein family. These measurements will be made using kinase inhibitors that possess vibrational probes of electric field, in which the probes report on the electrostatics they experience when bound in the ATP- binding site. Because these electrostatic maps relate to how the physical environment in the ATP- binding site appears from the perspective of the inhibitors, they will yield direct insight into how changes to the chemical structure of the inhibitors would affect the interaction with kinases. Differences uncovered between kinases in these measurements could be exploited to design more selective drugs. In Aim 2, this possibility will be quantified by performing large-scale binding assays in which the selectivity of panels of kinase inhibitors will be revealed and directly compared to the electrostatics measurements to reveal how electrostatic variation dictates selectivity. While selectivity profiling is commonplace in the pharmaceutical industry, the comparison with the electrostatic maps determined in Aim 1 will allow the physical basis of inhibitor selectivity to be determined for the first time, guiding the way to the development of inhibitors with new selectivity profiles. In Aim 3 the characterization of the ATP-binding site will be completed by studying how this environment is affected by the dynamic rearrangements of protein groups and bound water molecules. The protein kinases now constitute a major group of pharmacological targets, and taken together this work will constitute the first comprehensive experimental study of how the physical properties of these proteins dictate their interaction with drug molecules.

项目摘要/摘要