Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.
Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.
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DOI：
10.1021/acs.jcim.2c00300
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发表时间：
2022-05-23
影响因子：
5.6
通讯作者：
Rahman, Taufiq
中科院分区：
文献类型：
--
作者：
Wezen, Xavier Chee;Chandran, Aneesh;Eapen, Rohan Sakariah;Waters, Elaine;Bricio-Moreno, Laura;Tosi, Tommaso;Dolan, Stephen;Millership, Charlotte;Kadioglu, Aras;Grundling, Angelika;Itzhaki, Laura S.;Welch, Martin;Rahman, Taufiq
脂磷壁酸合成酶（LtaS）是革兰氏阳性菌细胞壁生物合成的关键酶。缺乏脂磷壁酸（LTA）的革兰氏阳性细菌表现出受损的细胞分裂和生长缺陷。因此，LtaS似乎是一个有吸引力的抗微生物靶标。关于LtaS的药理学仍然在很大程度上未被探索，仅报道了两种小分子LtaS抑制剂，即“化合物1771”和刚果红染料。由于缺乏LtaS的结合结构，针对LtaS的基于结构的药物发现努力仍未尝试。为了解决这个问题，我们结合使用分子对接技术与分子动力学（MD）模拟来模拟化合物1771与LtaS（eLtaS）的细胞外催化结构域的合理结合模式。该模型进行了验证丙氨酸诱变研究结合等温滴定量热法。此外，由我们的计算模型驱动的先导物优化产生了化合物1771的改进形式，即化合物4，其在生物物理测定中显示出比化合物1771更大的与eLtaS结合的亲和力。化合物4降低了S.金黄色葡萄球菌剂量依赖性地诱导了LTA缺陷型细菌的异常形态，并显著降低了感染S.金黄色。我们的MD模拟轨迹的分析揭示了在eLtaS中可能形成的瞬态隐蔽口袋。针对隐蔽口袋的虚拟筛选（VS）导致鉴定出一类新的抑制剂，其可以增强β-内酰胺类药物对耐甲氧西林S.金黄色。我们的整体工作流程和数据应该鼓励进一步的药物设计活动对LtaS。最后，我们的工作强调了考虑蛋白质构象灵活性对成功VS奋进的重要性。
Lipoteichoic acid synthase (LtaS) is a key enzyme for the cell wall biosynthesis of Gram-positive bacteria. Gram-positive bacteria that lack lipoteichoic acid (LTA) exhibit impaired cell division and growth defects. Thus, LtaS appears to be an attractive antimicrobial target. The pharmacology around LtaS remains largely unexplored with only two small-molecule LtaS inhibitors reported, namely “compound 1771” and the Congo red dye. Structure-based drug discovery efforts against LtaS remain unattempted due to the lack of an inhibitor-bound structure of LtaS. To address this, we combined the use of a molecular docking technique with molecular dynamics (MD) simulations to model a plausible binding mode of compound 1771 to the extracellular catalytic domain of LtaS (eLtaS). The model was validated using alanine mutagenesis studies combined with isothermal titration calorimetry. Additionally, lead optimization driven by our computational model resulted in an improved version of compound 1771, namely, compound 4 which showed greater affinity for binding to eLtaS than compound 1771 in biophysical assays. Compound 4 reduced LTA production in S. aureus dose-dependently, induced aberrant morphology as seen for LTA-deficient bacteria, and significantly reduced bacteria titers in the lung of mice infected with S. aureus. Analysis of our MD simulation trajectories revealed the possible formation of a transient cryptic pocket in eLtaS. Virtual screening (VS) against the cryptic pocket led to the identification of a new class of inhibitors that could potentiate β-lactams against methicillin-resistant S. aureus. Our overall workflow and data should encourage further drug design campaign against LtaS. Finally, our work reinforces the importance of considering protein conformational flexibility to a successful VS endeavor.
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影响因子：
6.4
作者：
Bæk KT;Bowman L;Millership C;Dupont Søgaard M;Kaever V;Siljamäki P;Savijoki K;Varmanen P;Nyman TA;Gründling A;Frees D
通讯作者：
Frees D
影响因子：
4
作者：
Farha, Maya A.;Leung, Alexander;Sewell, Edward W.;D'Elia, Michael A.;Allison, Sarah E.;Ejim, Linda;Pereira, Pedro M.;Pinho, Mariana G.;Wright, Gerard D.;Brown, Eric D.
通讯作者：
Brown, Eric D.
影响因子：
3.2
作者：
Garufi, Gabriella;Hendrickx, Antoni P.;Missiakas, Dominique
通讯作者：
Missiakas, Dominique
影响因子：
4.9
作者：
Campbell, Jennifer;Singh, Atul K.;Walker, Suzanne
通讯作者：
Walker, Suzanne
DOI：
10.1073/pnas.1004304107
发表时间：
2010-11-02
影响因子：
11.1
作者：
Atilano, Magda L.;Pereira, Pedro M.;Filipe, Sergio R.
通讯作者：
Filipe, Sergio R.