Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.
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DOI：
10.1073/pnas.2104093118
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发表时间：
2021-09-14
影响因子：
11.1
通讯作者：
Schlessinger A
中科院分区：
文献类型：
--
作者：
Garibsingh RA;Ndaru E;Garaeva AA;Shi Y;Zielewicz L;Zakrepine P;Bonomi M;Slotboom DJ;Paulino C;Grewer C;Schlessinger A
谷氨酰胺转运蛋白ASCT 2是各种癌症类型的新兴治疗靶点。在这里，我们使用一个综合的计算和实验方法来开发独特的ASCT 2抑制剂，针对合理的药物设计有用的构象状态。我们应用计算化学工具，如分子对接和分子动力学模拟，结合冷冻电子显微镜和合成化学的结构测定，设计多种ASCT 2抑制剂。我们的研究结果揭示了ASCT 2立体特异性抑制的独特机制，并强调了将最先进的计算和实验方法结合起来表征具有挑战性的人类膜蛋白靶点的实用性。ASCT 2（SLC 1A 5）是一种钠依赖性中性氨基酸转运蛋白，控制外周组织中的氨基酸稳态。在癌症中，ASCT 2上调，它调节细胞内谷氨酰胺水平，促进细胞增殖。通过ASCT 2抑制的营养剥夺为癌症治疗提供了一种潜在的策略。在这里，我们合理地设计了立体特异性抑制剂，利用特定的subpockets在底物结合位点，使用计算建模和冷冻电子显微镜（cryo-EM）。结合分子动力学模拟的最终结构揭示了ASCT 2结合位点中的多个非线性相关构象以及先前未知的立体特异性抑制机制。此外，这种综合分析指导了一系列独特ASCT 2抑制剂的设计。我们的研究结果提供了一个框架，为未来发展的癌症治疗靶向营养运输通过ASCT 2，以及证明了计算建模和cryo-EM结合溶质载体配体发现的效用。
The glutamine transporter ASCT2 is an emerging therapeutic target for various cancer types. Here, we use an integrated computational and experimental approach to develop unique ASCT2 inhibitors targeting a conformational state useful for rational drug design. We apply computational chemistry tools such as molecular docking and molecular dynamics simulations, in combination with structure determination with cryo-electron microscopy and synthetic chemistry, to design multiple ASCT2 inhibitors. Our results reveal a unique mechanism of stereospecific inhibition of ASCT2 and highlight the utility of combining state-of-the-art computational and experimental approaches in characterizing challenging human membrane protein targets. ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.
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影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
影响因子：
13.6
作者：
Bonomi M;Camilloni C;Cavalli A;Vendruscolo M
通讯作者：
Vendruscolo M
影响因子：
5.8
作者：
Bonomi, Massimiliano;Camilloni, Carlo
通讯作者：
Camilloni, Carlo
影响因子：
64.8
作者：
Canul-Tec JC;Assal R;Cirri E;Legrand P;Brier S;Chamot-Rooke J;Reyes N
通讯作者：
Reyes N
DOI：
10.1073/pnas.1900441116
发表时间：
2019-05-21
影响因子：
11.1
作者：
Eshun-Wilson, Lisa;Zhang, Rui;Nogales, Eva
通讯作者：
Nogales, Eva