Structure-based virtual screening for drug discovery: principles, applications and recent advances.
Structure-based virtual screening for drug discovery: principles, applications and recent advances.
复制标题
DOI：
10.2174/1568026614666140929124445
复制
发表时间：
2014
影响因子：
3.4
通讯作者：
Cournia Z
中科院分区：
文献类型：
--
作者：
Lionta E;Spyrou G;Vassilatis DK;Cournia Z
基于结构的药物发现（SBDD）正在成为帮助快速和具有成本效益的先导发现和优化的重要工具。基于结构的合理药物设计的应用被证明比传统的药物发现方式更有效，因为它旨在了解疾病的分子基础，并在此过程中利用生物靶标的三维结构知识。在这篇综述中，我们专注于虚拟筛选（VS）的原理和应用的背景下，SBDD和检查不同的程序，从初始阶段的过程，包括受体和库的预处理，对接，评分和后处理的topscoring命中。最近的改进，基于结构的虚拟筛选（SBVS）的效率，通过系综对接，诱导拟合和共识对接进行了讨论。该审查突出了在该领域的进展的几个成功的研究，导致直接从VS的nM抑制的框架内，并提供了最近的趋势库设计，以及讨论的方法的局限性。SBVS在设计工程蛋白质的底物，使新的代谢和信号转导途径的发现和多功能蛋白质的抑制剂的设计中的应用也进行了审查。最后，我们贡献了两个有前途的VS协议，我们最近开发的，旨在提高抑制剂的选择性。在第一个方案中，我们描述了通过SBVS发现微摩尔抑制剂，旨在抑制突变型H1047R PI3Kα激酶。其次，我们讨论了一种策略，用于识别RXRα核受体的选择性结合剂。在该方案中，构建了一组靶结构，用于基于结合位点形状表征和聚类的系综对接，旨在通过SBVS过程提高选择性抑制剂对所需蛋白质靶标的命中率。
Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.
登录
查看更多内容
影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
21.8
作者：
通讯作者：
--
DOI：
10.1186/bcr913
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Crowe DL;Chandraratna RA
通讯作者：
Chandraratna RA
影响因子：
5.6
作者：
Craig, Ian R.;Essex, Jonathan W.;Spiegel, Katrin
通讯作者：
Spiegel, Katrin
影响因子：
5.6
作者：
Chaudhury, Sidhartha;Gray, Jeffrey J.
通讯作者：
Gray, Jeffrey J.