Computational Design of Metal Ion Sequestering Agents Page: 2 of 8
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These new capabilities are being applied to ligand systems identified under other
DOE-sponsored projects where studies have suggested that modifying existing
architectures will lead to dramatic enhancements in metal ion binding affinity and
selectivity. With this in mind, we are collaborating with Professors R. T. Paine
(University of New Mexico), K. N. Raymond (University of California, Berkeley), and J.
E. Hutchison (University of Oregon), and Dr. B. A. Moyer (Oak Ridge National
Laboratory) to obtain experimental validation of the predicted new ligand structures.
Successful completion of this study will yield molecular-level insight into the role that
ligand architecture plays in controlling metal ion complexation and will provide a
computational approach to ligand design.
Research Progress and Implications
This project is a renewal of EMSP Project No. 73759 "Architectural Design Criteria
for f-Block Metal Sequestering Agents" that began in September 2000 and ended in
September 2003. This report summarizes progress at the end of the current 3-year period.
Research has focused on two major areas. These were (1) expanding the functionality of
our de novo structure-based design program, HostDesigner, and (2) application of
computational methods to ligand design.
To bring the powerful concepts embodied in de novo structure-based drug design to
the field of coordination chemistry, we have developed a computer program named
HostDesigner with support from PNNL LDRD and Chemical Sciences, Office of Basic
Energy Sciences, Office of Science, US DOE. This software builds millions of potential
host structures from molecular fragments, screens the candidate structures with respect to
their complementarity for a targeted metal ion guest, and outputs a list of lead candidates
for further evaluation. One of the goals of this EMSP project is to couple the
HostDesigner software with subsequent MM analyses to provide a more accurate
prioritization of the candidates.
In collaboration with Dr. Kevin E. Gilbert (Serena Software), we completed the full
automation of the MM analyses. To accomplish this, we developed an interface to a
commercially available MM post-processing software module (GMMX,
www.serenasoft.com) that provides access to five force field models including MMX,
MM3, AMBER, MMFF94, and OPLSAA. The MM analyses occur in two steps. In the
first step, a set of up to 10,000 top hits from HostDesigner are evaluated with respect to
calculated guest binding energies. In the second step, a smaller subset of the top hits are
conformationally searched and the candidates are sorted to give a final ranking on the
basis of total reorganization energy.
To test and validate the performance of the new software, we have focused on the
computer-aided design of improved building blocks for constructing metal-selective
crown ethers. This system was chosen because the geometric aspects of metal-ether
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Hay, Benjamin P. & Rapko, Brian M. Computational Design of Metal Ion Sequestering Agents, report, June 1, 2006; Richland, Washington. (https://digital.library.unt.edu/ark:/67531/metadc888064/m1/2/: accessed April 16, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.