Micro X-Ray Fluorescence As A High Throughput Screening Method For Combinatorial Chemistry
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Micro X-Ray Fluorescence As A High Throughput Screening Method For Combinatorial Chemistry George J. Havrilla, Thomasin Miller, Benjamin Warner, Cyndi Wells Los Alamos National Laboratory Los Alamos, NM 87545 USA ABSTRACT Micro X-ray fluorescence is used as a high-throughput screening method for combinatorial applications. These include chemical weapon degradation products, catalytic phosphate hydrolysis and radiologic dispersion device metals. In each application the intrinsic elemental signature was utilized to identify the lead hits for the combinatorial screening in locating peptide sequences exhibiting the desired binding characteristics. In addition to being nondestructive, rapid and non-perturbing to the binding event, this method can be used to quantify the amount of target material.
INTRODUCTION The difficult part of combinatorial chemistry is screening the large library of compounds for desired properties of potentially useful molecules. One must either screen each individual reaction or modify the test substrate so that it produces a faster and more easily detected change such as color. These modifications make the desired properties easy to detect at the expense of making the test case less important, because the colored test substrate may not have the same reactivity as the uncolored desirable substrate. Active research in high-throughput screening has led to recent discoveries of methods based on mass spectrometry [1-3], infrared thermography [4], Fourier transform infrared spectroscopy [5-9], near infrared spectroscopy [10, 11] laserinduced resonance-enhanced multiphoton excitation [12], and laser-induced fluorescence imaging[13]. This work highlights some of the recent applications of using micro X-ray fluorescence as a high-throughput screening method for combinatorial chemistry. Micro X-ray fluorescence (MXRF) eliminates the need for tags, which perturb the molecules in order to detect binding events. MXRF determines the presence and relative amounts of elements heavier than sodium. These elements include sulfur and phosphorus, which are important constituents of proteins (enzymes) and DNA (e.g. gene therapy). Thus, we can screen for intrinsic properties of these important biomolecules. MXRF requires no sample preparation, does not destroy the sample, and can accurately detect nanogram quantities of the desired element in mixtures using short screening times. We have used MXRF to screen several experiments using commercially available combinatorial peptide libraries for desired properties. In these cases, 11-mer peptides on polystyrene beads were used to identify sequences, which would be useful in binding degradation products of chemical warfare agents, metal catalyzed phosphate hydrolysis and binding potential radiological dispersion cations. The utility elemental high-throughput screening with MXRF is highlighted in these examples. MXRF can detect elemental composition for a given sample by measuring its characteristic X-ray emission wavelengths or energies. MXRF can be used to identi
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