Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules.
Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules.
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DOI：
10.1021/ct300117j
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发表时间：
2012-07-10
影响因子：
5.5
通讯作者：
Bahar, Ivet
中科院分区：
文献类型：
--
作者：
Bakan, Ahmet;Nevins, Neysa;Lakdawala, Ami S.;Bahar, Ivet
靶蛋白的可药物性评价近年来成为hit-to-lead优化中的一个重要概念。一种可靠和实际相关的可制毒性措施将有助于就投资于某一特定目标的风险作出知情决定。在这里，我们将“可药物性”定义为对作用于特定蛋白质靶点的潜在药物的结合位点和亲和力的定量估计。在目前的研究中，我们描述了一种新的方法，成功地预测了一系列具有挑战性的靶标的药物性和最大结合亲和力，包括那些通过变构机制起作用的靶标。该方法的两个显著特征是：(i)基于对已批准药物的分析而选择的多种探针分子的结合动力学模拟；（ii）基于对结合探针簇的几何和能量学的评估，确定可药物位点并估计相应的结合亲和力。该方法用于多种靶标，如小鼠双突变体-2、蛋白酪氨酸磷酸酶1B （PTP1B）、淋巴细胞功能相关抗原1、脊椎动物激酶5 （Eg5）和p38丝裂原活化蛋白激酶，为该方法正确捕获已知药物的位置和结合亲和力提供了示例。它还提供了对新的可药物位点和靶标结构变化的见解，这些变化即使不能促进和稳定药物结合，也会适应。值得注意的是，即使在PTP1B或Eg5等具有挑战性的情况下，识别高亲和力点的能力也有望成为评估蛋白质靶点的药物可药性和识别药物结合变抗或新位点的合理工具。
Druggability assessment of a target protein has emerged in recent years as an important concept in hit-to-lead optimization. A reliable and physically relevant measure of druggability would allow informed decisions on the risk of investing in a particular target. Here, we define “druggability” as a quantitative estimate of binding sites and affinities for a potential drug acting on a specific protein target. In the present study, we describe a new methodology that successfully predicts the druggability and maximal binding affinity for a series of challenging targets, including those that function through allosteric mechanisms. Two distinguishing features of the methodology are (i) simulation of the binding dynamics of a diversity of probe molecules selected on the basis of an analysis of approved drugs and (ii) identification of druggable sites and estimation of corresponding binding affinities on the basis of an evaluation of the geometry and energetics of bound probe clusters. The use of the methodology for a variety of targets such as murine double mutant-2, protein tyrosine phosphatase 1B (PTP1B), lymphocyte function-associated antigen 1, vertebrate kinesin-5 (Eg5), and p38 mitogen-activated protein kinase provides examples for which the method correctly captures the location and binding affinities of known drugs. It also provides insights into novel druggable sites and the target’s structural changes that would accommodate, if not promote and stabilize, drug binding. Notably, the ability to identify high affinity spots even in challenging cases such as PTP1B or Eg5 shows promise as a rational tool for assessing the druggability of protein targets and identifying allosteric or novel sites for drug binding.
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影响因子：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.
影响因子：
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作者：
Bodey, Andrew J.;Kikkawa, Masahide;Moores, Carolyn A.
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作者：
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作者：
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