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.

Dacomitinib (PF-00299804) 最近被美国食品和药物管理局 (FDA) 批准作为酪氨酸激酶抑制剂 (TKI)。不幸的是，它的使用最终会导致副作用和抗病性。一些激酶抑制剂的脱靶效应是由药物构象可塑性引起的；然而，达克替尼在溶液中的构象状态目前未知。为了填补这一空白，我们使用计算化学来探索达克替尼在二甲基亚砜（DMSO）溶液中的优化分子几何形状、性质和紫外可见（UV-Vis）吸收光谱。势能扫描发现了达克替尼的两个平面和两个扭曲构象异构体。平面构象异构体的模拟紫外-可见光谱特征在溶液中再现了 275 和 343 nm 处的两个实验光谱带。进一步发现，达克替尼通过其两个 C-NH-C 桥的三个柔性连接体形成构象异构体，这些连接体控制 3-氯-4-氟苯胺环（环 C）和喹唑啉环（环 A 和 B）的方向4-哌啶-1-基-丁烯-2-醛侧链，以及一个局部控制甲氧基的 C-O-C 局部桥。当分离时，这些柔性连接体通过强分子内氢键形成紧密的六边形和五边形环，使得“平面”构象异构体Daco-P1和Daco-P2在分离时更加稳定。配体的这种灵活性及其与蛋白质对接和结合的能力除了取决于它们的能量和分离光谱外，还取决于它们与环境的相互作用。然而，对药物/配体构象异构体的精确量子力学研究为与蛋白质形成复合物的能力提供了必要的参考信息。