Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Health Building 2, Houston, TX 77204, USA.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Health Building 2, Houston, TX 77204, USA; Department of Chemistry, University of Houston, Health Building 2, Houston, TX 77204, USA.
Bioorg Med Chem Lett. 2020 Dec 15;30(24):127543. doi: 10.1016/j.bmcl.2020.127543. Epub 2020 Sep 12.
Inosine-5'-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; CpIMPDH K = 0.042 ± 0.015 µM, HsIMPDH2 K = 0.13 ± 0.05 µM) supports different binding modes with the two enzymes. For CpIMPDH the inhibitor extends into a pocket in an adjacent subunit. In contrast, docking suggests the inhibitor interacts with Ser276 in the NAD binding site in HsIMPDH2, as well as an adjacent pocket within the same subunit. These results provide further guidance for generating IMPDH inhibitors for enzymes found in an array of pathogenic microorganisms, including Mycobacterium tuberculosis.
肌苷-5'-单磷酸脱氢酶（IMPDH）是微生物的一个潜在靶点。然而，鉴定 IMPDH 同源物的抑制剂设计决定因素仍在不断发展。本文报道了一系列来源于 Cryptosporidium parvum 和人 IMPDH 的霉酚酸苯胺抑制剂。此外，对 12 种化合物（例如 SH-19；CpIMPDH K = 0.042 ± 0.015 μM，HsIMPDH2 K = 0.13 ± 0.05 μM）的分子对接支持与两种酶的不同结合模式。对于 CpIMPDH，抑制剂延伸到相邻亚基中的一个口袋中。相比之下，对接表明抑制剂与 HsIMPDH2 的 NAD 结合位点中的 Ser276 以及同一亚基内的相邻口袋相互作用。这些结果为生成针对包括结核分枝杆菌在内的一系列致病微生物中发现的酶的 IMPDH 抑制剂提供了进一步的指导。
