College of Animal Science and Technology , Jilin Agricultural University , Changchun 130118 , China.
Department of Chemistry , University of Arkansas at Little Rock , Little Rock , Arkansas 72204 , United States.
Biochemistry. 2020 Feb 25;59(7):831-835. doi: 10.1021/acs.biochem.9b01092. Epub 2020 Feb 11.
Transition state analogue inhibitor design (TSID) and fragment-based drug design (FBDD) are drug design approaches typically used independently. Methylthio-DADMe-Immucillin-A (MTDIA) is a tight-binding transition state analogue of bacterial 5'-methylthioadenosine nucleosidases (MTANs). Previously, MTAN structures were found to bind MTDIA and ethylene glycol fragments, but MTDIA modified to contain similar fragments did not enhance affinity. Seventy-five published MTAN structures were analyzed, and co-crystallization fragments were found that might enhance the binding of MTDIA to other bacterial MTANs through contacts external to MTDIA binding. The fragment-modified MTDIAs were tested with Helicobacter pylori MTAN and Staphylococcus aureus MTANs (MTAN and MTAN) as test cases to explore inhibitor optimization by potential contacts beyond the transition state contacts. Replacement of a methyl group with a 2'-ethoxyethanol group in MTDIA improved the dissociation constant 14-fold (0.09 nM vs 1.25 nM) for MTAN and 81-fold for MTAN (0.096 nM vs 7.8 nM). TSID combined with FBDD can be useful in enhancing already powerful inhibitors.
过渡态类似物抑制剂设计（TSID）和基于片段的药物设计（FBDD）是通常独立使用的药物设计方法。Methylthio-DADMe-Immucillin-A（MTDIA）是一种与细菌 5'-甲基硫代腺苷核苷酶（MTANs）紧密结合的过渡态类似物。先前，MTAN 结构被发现与 MTDIA 和乙二醇片段结合，但经过修饰以包含类似片段的 MTDIA 并没有增强亲和力。分析了 75 个已发表的 MTAN 结构，发现了共晶片段，这些片段可能通过与 MTDIA 结合以外的接触增强 MTDIA 与其他细菌 MTAN 的结合。对幽门螺杆菌 MTAN 和金黄色葡萄球菌 MTAN（MTAN 和 MTAN）进行了片段修饰的 MTDIA 测试，以探索通过过渡态以外的潜在接触优化抑制剂。用 2'-乙氧基乙醇基团取代 MTDIA 中的甲基基团，使 MTAN 的解离常数提高了 14 倍（0.09 nM 对 1.25 nM），使 MTAN 的解离常数提高了 81 倍（0.096 nM 对 7.8 nM）。将 TSID 与 FBDD 相结合，可用于增强已有的强效抑制剂。
