Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.
Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.
J Med Chem. 2018 Nov 21;61(22):10206-10217. doi: 10.1021/acs.jmedchem.8b01363. Epub 2018 Oct 31.
Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PA endonuclease, a class of highly active and selective fragments was developed that displays IC values <50 nM. This SAR led to structurally distinct molecules that also displayed IC values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.
金属酶是药物发现的一个重要靶标。早期金属酶抑制剂的发展受到限制，原因是缺乏与金属酶的金属离子辅因子结合的分子的明确结构-活性关系（SAR）。在此，我们采用生物无机的观点来开发流感 RNA 聚合酶 PA 内切酶的金属酶抑制剂 SAR。确定的趋势强调了金属结合药效团（MBP）的电子性质，以及 MBP 立体化学，对于实现更好的抑制和选择性的重要性。通过优化 PA 内切酶的 MBPs，开发了一类具有高活性和选择性的片段，其 IC 值<50 nM。该 SAR 导致结构不同的分子也显示出约 10 nM 的 IC 值，说明了以金属为中心的开发活动在产生高活性和选择性的金属酶抑制剂方面的实用性。
