Molecular Modeling in Metal Based Imaging Agent Design

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EXCEED THE SPACE PROVIDED. In this proposal we seek to expand on work begun in our original funded application (David E. Reichert, P.I. 8 R01 EB00340) on the use of molecular modeling in the design of metal based imaging agents. The development of metal based imaging agents would be greatly aided by the existence of well validated tools for structure-based design. In order to develop such tools we seek to develop methods for predicting the binding affinities of radiometal based imaging agents to two serum transport proteins, human serum albumin, and sex hormone binding globulin, and to the estrogen receptor. Our specific aims to accomplish this goal are as follows: 1. Develop in silica a library of Cu(II) ligands, based on trans-disubstituted cyclen and cyclam backbones. 2. Dock our screening libraries into the binding sites of human serum albumin (HSA), sex hormone binding globulin (SHBG), and two isoforms of the estrogen receptor (ER a andER 3. Calculate the free energies of binding using the MM-PBSA methodology for subsets of the complexes in each of the studied proteins. 4. Experimentally synthesize the same subsets of molecules and measure the binding affinities to each studied protein using equilibrium dialysis. 5. Develop scoring functions for predicting the measured binding affinities, using both the calculated free energies and docked poses. 6. Develop a set of web based tools for other researchers to be able to directly utilize our current and future QSAR models predicting biological behavior on their own compounds. Molecular docking has become a valuable tool in drug design when the molecular structure of the receptor is known; with advances in docking programs and computer hardware it is now possible to perform virtual screening studies. These same techniques could be applied to the development of metal based imaging agents as well; a major problem is the paucity of experimental data for large sets of such compounds. In this proposal we seek to develop such data and to develop and validate methods for distinguishing good from moderate binding radiometal complexes. PERFORMANCE SITE ========================================Section End===========================================