The development of an NMR chemical shift prediction application with the accuracy necessary to grade proton NMR spectra for identity

Abstract

We have developed an NMR chemical shift prediction system that enables high throughput automatic grading of NMR spectra. In support of high throughput synthetic efforts for our drug discovery program, a rapid and accurate analysis for identity was needed. The system was designed and implemented to take advantage of the NMR assignments that had been tabulated on internally generated research compounds. The system has been operational for four years and has been used in conjunction with an internally written grading program to successfully analyze several hundred thousand samples based only on their 1D 1 H spectrum. A focused test of the system's accuracy on 1006 molecules demonstrated the ability to estimate the proton chemical shift with an average error of +/−0.16 ppm. This level of chemical shift accuracy allows for reliable structure confirmation by automated analysis using only proton NMR.

19F NMR chemical shift prediction with fluorine fingerprint descriptor

“…These fluorine-environment fingerprints were inspired by the topological torsion descriptors published by Nilakantan et al [26] Our fluorine-environment fingerprints differ from standard topological torsions (where L is kept fixed to four) in that we include all paths between one to five, six or seven bonds and only paths that start from the fluorine atom or the CF 3 moiety. This descriptor is distantly related to the HOSE descriptor [27] that has been used for 1 H and 13 C chemical shift predictions [28]. The fluorine-environment fingerprints have previously been utilized for the design of a diverse fluorinated fragment library containing different local environment of fluorine (LEF) [11].…”

An Integrated Synthesis-Purification System to Accelerate the Generation of Compounds in Pharmaceutical Discovery

“…The chemical shift assignments for the sample's protons are estimated through utilization of the Abbott NMR prediction system engine [11]. This system is designed to allow the rapid update of new assignments for a core and allows the predictions to be heavily weighted by the closest matching structure, such as the core itself.…”

Improving the efficiency of branch-and-bound complete-search NMR assignment using the symmetry of molecules and spectra

“…Indeed, it is the most common procedure for structure validation by NMR, thus playing a key role in structure elucidation and validation by NMR spectroscopy, which in turn is a core component of new compound discovery/synthesis and related fields. Furthermore, most of the research in the field of NMR chemical shift prediction [5][6][7][8][9][10][11][12][13][14] and automatic elucidation [15][16][17][18][19][20][21] depends on repositories of well-assigned NMR data. Although manual assignment by an expert is the most widely used and most reliable method, the already big and continuously growing amount of information produced nowadays demands computational tools for assisting this task.…”