RNA drug discovery: Conformational restriction enhances specific modulation of the T-box riboswitch function.
RNA drug discovery: Conformational restriction enhances specific modulation of the T-box riboswitch function.
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DOI：
10.1016/j.bmc.2020.115696
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发表时间：
2020-10-15
影响因子：
3.5
通讯作者：
Hines JV
中科院分区：
文献类型：
--
作者：
Armstrong I;Aldhumani AH;Schopis JL;Fang F;Parsons E;Zeng C;Hossain MI;Bergmeier SC;Hines JV
抗菌药物耐药性是一个全球性的健康问题，需要多种解决方案，包括开发新的抗菌化合物作用于新的目标。靶向调节RNA是药物发现的新兴领域。T-box核糖开关是一种控制革兰氏阳性菌基因表达的RNA调节机制，是抗菌药物设计的一个特殊的新靶点。我们报告了一系列构象限制的恶唑烷酮-三唑化合物的设计、合成和活性，这些化合物靶向高度保守的T-box核糖开关的抗终止子RNA元件。计算的结合能与实验推导的Kd值表明在这一系列化合物的对接研究的预测能力。构象限制的化合物特异性抑制T盒核糖开关功能，而不是整体转录。复合物破坏，计算对接和RNA结合特异性数据表明，抑制可能是由于配体结合到变构位点。这些结果突出了配体亲和力和RNA构象结果对于靶向RNA药物设计的重要性。
Antibacterial drug resistance is a global health concern that requires multiple solution approaches including development of new antibacterial compounds acting at novel targets. Targeting regulatory RNA is an emerging area of drug discovery. The T-box riboswitch is a regulatory RNA mechanism that controls gene expression in Gram-positive bacteria and is an exceptional, novel target for antibacterial drug design. We report the design, synthesis and activity of a series of conformationally restricted oxazolidinone-triazole compounds targeting the highly conserved antiterminator RNA element of the T-box riboswitch. Computational binding energies correlated with experimentally-derived Kd values indicating the predictive capabilities for docking studies within this series of compounds. The conformationally restricted compounds specifically inhibited T-box riboswitch function and not overall transcription. Complex disruption, computational docking and RNA binding specificity data indicate that inhibition may result from ligand binding to an allosteric site. These results highlight the importance of both ligand affinity and RNA conformational outcome for targeted RNA drug design.
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影响因子：
7.7
作者：
Kaczmarek-Hajek K;Zhang J;Kopp R;Grosche A;Rissiek B;Saul A;Bruzzone S;Engel T;Jooss T;Krautloher A;Schuster S;Magnus T;Stadelmann C;Sirko S;Koch-Nolte F;Eulenburg V;Nicke A
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通讯作者：
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影响因子：
16.8
作者：
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影响因子：
7.3
作者：
Orac, Crina M.;Zhou, Shu;Means, John A.;Boehm, David;Bergmeier, Stephen C.;Hines, Jennifer V.
通讯作者：
Hines, Jennifer V.