Deducing the Conformational Properties of a Tyrosine Kinase Inhibitor in Solution by Optical Spectroscopy and Computational Chemistry.

Dacomitinib (PF-00299804) was recently approved by the Food and Drug Administration (FDA) as a tyrosine kinase inhibitor (TKI). Unfortunately, side effects and disease resistance eventually result from its use. Off-target effects in some kinase inhibitors have arisen from drug conformational plasticity; however, the conformational states of Dacomitinib in solution are presently unknown. To fill this gap, we have used computational chemistry to explore optimized molecular geometry, properties, and ultraviolet-visible (UV-Vis) absorption spectra of Dacomitinib in dimethyl sulfoxide (DMSO) solution. Potential energy scans led to the discovery of two planar and two twisted conformers of Dacomitinib. The simulated UV-Vis spectral signatures of the planar conformers reproduced the two experimental spectral bands at 275 and 343 nm in solution. It was further discovered that Dacomitinib forms conformers through its three flexible linkers of two C-NH-C bridges, which control the orientations of the 3-chloro-4-fluoroaniline ring (Ring C) and the quinazoline ring (Rings A and B) and the 4-piperidin-1-yl-buten-2-nal side chain, and one C-O-C local bridge which controls the methoxy group locally. When in isolation, these flexible linkers form close hexagon and pentagon loops through strong intramolecular hydrogen bonding so that the "planar" conformers Daco-P1 and Daco-P2 are more stable in isolation. Such flexibility of the ligand and its ability to dock and bind with protein also depend on their interaction with the environment, in addition to their energy and spectra in isolation. However, an accurate quantum mechanical study on drug/ligand conformers in isolation provides necessary reference information for the ability to form a complex with proteins.

Experimental and Theoretical Soft X-ray Study of Nicotine and Related Compounds.

The valence and core electronic structure of nicotine, nicotinic acid, and nicotinamide have been studied by photoelectron and soft X-ray absorption spectroscopy, supported by theoretical calculations, which take into account conformational isomerism. The core-level photoionization spectra of all molecules have been assigned, and theory indicates that the effects of conformational differences are small, generally less than the natural line widths of the core ionic states. However, in the case of nicotinamide, the theoretical valence ionization potentials of cis and trans conformers differ significantly in the outer valence space, and the experimental spectrum is in agreement with the calculated outer valence cis conformer spectrum. In addition, the C, N, and O K edge near-edge absorption fine structure spectra are reported and interpreted by comparison with reference compounds. We find evidence at the N and O K edges of interaction between the delocalized orbitals of the pyridine ring and the substituents for nicotinic acid and nicotinamide. The strength of the interaction varies because the first is planar, while the second is twisted, reducing the extent of orbital mixing.

Impact of intramolecular hydrogen bonding of gallic acid conformers on chemical shift through NMR spectroscopy.

Intramolecular hydrogen bonding of gallic acid conformers was probed as a function of their dihedral angles using 13C nuclear magnetic resonance (NMR) chemical shift (δC). The quantum mechanically calculated 13C NMR chemical shift based on the most stable conformer (GA-I) in dimethylsulfoxide (DMSO) solution agrees to available measurement in the same solvent (RMSD = 0.95 ppm), better than to the measurement in solid phase (RMSD = 1.93 ppm). The accuracy of the calculated NMR chemical shift of the nominal but non-equivalent phenyl carbons C(3)/C(7) and C(4)/C(6) (ortho and meta to the acid -C(1)OOH group) of GA may not be evaluated using the experimental measurements at room temperature. The splitting in chemical shift of the nominal phenyl carbons is able to be experimentally measured only in low temperature NMR and using quantum mechanical calculations. We further recognised that the C NMR chemical shifts of the nominal phenyl carbons (C(3)/C(7) and C(4)/C(6)) encode information for intramolecular hydrogen bonding network formed by GA conformers. The ability to obtain accurate splitting of NMR chemical shifts for nominal carbons, therefore, determines the usefulness of the NMR technique as a probe for conformation of GA.