Kabir Md Lutful, Wang Feng, Clayton Andrew H A
Optical Sciences Centre, Department of Physics and Astronomy, School of Science, Computing and Engineering Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia.
Department of Chemistry and Biotechnology, School of Science, Computing and Engineering Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia.
Biology (Basel). 2022 Jul 28;11(8):1135. doi: 10.3390/biology11081135.
At present, about one-third of the total protein targets in the pharmaceutical research sector are kinase-based. While kinases have been attractive targets to combat many diseases, including cancer, selective kinase inhibition has been challenging, because of the high degree of structural homology in the active site where many kinase inhibitors bind. Despite efficacy as cancer drugs, kinase inhibitors can exhibit limited target specificity and rationalizing their target profiles in the context of precise molecular mechanisms or rearrangements is a major challenge for the field. Spectroscopic approaches such as infrared, Raman, NMR and fluorescence have the potential to provide significant insights into drug-target and drug-non-target interactions because of sensitivity to molecular environment. This review places a spotlight on the significance of fluorescence for extracting information related to structural properties, discovery of hidden conformers in solution and in target-bound state, binding properties (e.g., location of binding sites, hydrogen-bonding, hydrophobicity), kinetics as well as dynamics of kinase inhibitors. It is concluded that the information gleaned from an understanding of the intrinsic fluorescence from these classes of drugs may aid in the development of future drugs with improved side-effects and less disease resistance.
目前，制药研究领域中约三分之一的蛋白质靶点是基于激酶的。虽然激酶一直是对抗包括癌症在内的多种疾病的有吸引力的靶点，但由于许多激酶抑制剂结合的活性位点结构高度同源，选择性激酶抑制一直具有挑战性。尽管激酶抑制剂作为抗癌药物有效，但它们可能表现出有限的靶点特异性，并且在精确的分子机制或重排背景下合理化其靶点特征是该领域的一项重大挑战。红外、拉曼、核磁共振和荧光等光谱方法由于对分子环境敏感，有可能为药物-靶点和药物-非靶点相互作用提供重要见解。本综述重点关注荧光在提取与激酶抑制剂的结构性质、溶液中和靶点结合状态下隐藏构象的发现、结合性质（如结合位点的位置、氢键、疏水性）、动力学以及动态相关信息方面的重要性。得出的结论是，从对这类药物固有荧光的理解中收集到的信息可能有助于开发具有改善副作用和更低耐药性的未来药物。
