Automated accurate mass data processing using a gas chromatograph/time-of-flight mass spectrometer in drug discovery

A gas chromatograph/time-of-flight (GCT) mass spectrometer, with high mass measurement accuracy to within 5 ppm, has been used for the automated accurate mass analysis of multicomponent mixtures and drug discovery compounds. A multicomponent mixture was analyzed several times over the course of a week to assess the reproducibility and ruggedness of the automated method while operating the GCT in electron ionization mode. For example, the data for 31 radical cations generated via electron ionization was processed using automated software (i.e. OpenLynx) to provide for mass accuracies less than 5 ppm for nearly 100% of the ions from multiple injection data. Mass accuracies of the radical anions of polyaromatic hydrocarbons generated via negative chemical ionization, and protonated pyridines and quinolines generated via methane chemical ionization, were mainly less than 5 ppm from multiple injection data. In addition, the automated method has been used for the accurate mass analysis of drug discovery compounds.     

On the nature of pulsars

The paper contains a relatively non-technical summary of some recent work by the author and Jeremy Butterfield. The goal is to find a way of assigning meaningful truth values to propositions in quantum theory: something that is not possible in the normal, instrumentalist interpretation. The key mathematical tool is presheaf theory where multi-valued, contextual truth values arise naturally. We show how this can be applied to quantum theory, with the ‘contexts’ chosen to be Boolean subalgebras of the set of all projection operators.     

Integrity profiling of high throughput screening hits using LC-MS and related techniques

Integrity profiling of HTS hits is valuable for verification of the hit identity and purity. This provides early discovery researchers with more confident SAR theories. Methodology for integrity profiling of HTS hits must be high throughput, consume little material, and selectively provide structure-based data. Analytical techniques that can be utilized for integrity profiling methods are reviewed for their appropriateness in sample preparation, component separation, detection, purity quantitation, identity confirmation, and follow-up.     

Supercooling of the disordered vortex lattice in Bi(2)Sr(2)CaCu(2)O(8+delta)

Time-resolved local induction measurements near the vortex lattice order-disorder transition in optimally doped Bi(2)Sr(2)CaCu(2)O(8+delta) crystals show that the high-field, disordered phase can be quenched to fields as low as half the transition field. Over an important range of fields, the electrodynamical behavior of the vortex system is governed by the coexistence of ordered and disordered vortex phases in the sample. We interpret the results as supercooling of the high-field phase and the possible first-order nature of the order-disorder transition at the "second magnetization peak."     

Automated sub-ppm mass accuracy on an ESI-TOF for use with drug discovery compound libraries

An automated, routine method to obtain sub-ppm accurate mass data on a benchtop electrospray ionization time-of-flight (ESI-TOF) mass spectrometer is described. Standards in the mass range 114 to 734 Da were analyzed over a 5-day period to demonstrate intra- and interday precision and mean mass accuracy less than 1 ppm. One hundred drug discovery pharmaceutical compounds were used to demonstrate an absolute average mass accuracy of 0.47 +/- 0.31 ppm. This is in contrast to previous reports of accurate mass analysis using time-of-flight mass spectrometry (TOFMS) technology that operates within 3 to 5 ppm. The same 100 samples were also analyzed using Fourier transform mass spectrometry (FTMS) technology and yielded comparable results to the TOFMS analysis.     

Sub-2 microm HPLC coupled with sub-ppm mass accuracy for analysis of pharmaceutical compound libraries

Recent advances in accurate mass analysis are poised to allow the high-throughput production of accurate mass data on many more compounds than was previously available. It is shown that sub-ppm mass accuracy (producing elemental compositions) can be obtained on a simple TOF mass spectrometer operating in the manufacturer's standard mode. Concomitantly, there have been important technological advances in LC with respect to speed of analysis using sub-2 microm particle columns. Much of the sub-2 microm work in the literature has been under the label ultra performance LC (UPLC), however, we show that very high-speed results can be obtained using other manufacturer's pumps by using elevated column temperatures. Using elevated temperatures, HPLC peak widths on the order of 1 s can be obtained. We report the coupling of these two technologies (sub-ppm mass accuracy MS with high-speed HPLC) for the rapid analysis of compounds entering pharmaceutical libraries.