Target Identification and Validation in Drug Development

The discovery of a new drug begins by understanding the疾病的生物学起源并确定潜在的干预药物靶标。从理论上讲，识别和验证药物目标的过程看起来很简单，但是说起来容易做起来难。

Many drug candidatesfail到达市场，在后期试验的最后一刻，许多有希望的治疗方案失败了。确定合适的药物目标并执行在早期的有效验证研究可以帮助避免昂贵的临床失败。

This article will highlight the properties of an attractive drug target, outline the approaches used to identify targets and discuss the key steps involved in target validation.

选择目标

药物发现的过程始于鉴定可能的生比利时罗马尼亚比分直播物学靶标并阐明其在疾病中的作用。靶标是一种生化实体（蛋白质，RNA或基因），药物可以结合并引起生理变化。靶标必须具有潜在药物可以结合的活性位点或结合口袋。一个最佳目标应该是可毒品，安全，高效的，并且能够满足商业要求。

Barbara Zdrazil博士，化学协调员，欧洲生物信息学研究所说：“传统上，G蛋白偶联受体（GPCR）和激酶多年来一直是非常好的药物靶标。如今，我们看到新的方式出现了用于治疗疾病的新方式，包括以前可牵涉的靶标。一个例子是通过第一个选择性KRAS抑制剂Sotorasenib批准癌症治疗的最新进展，2021年用于治疗肿瘤克拉斯G12C mutation. Also, bromodomain inhibitors have emerged as a promising class of anticancer agents. The concept of protein degradation by heterobifunctional small-molecule proteolysis-targeting chimeras (PROTACs) has also gained a lot of interest in recent years, as well as gene therapy (e.g., the use of CRISPR technology) which can offer personalized treatments for patients.”

识别药物 - 目标相互作用

药物多药理学轮廓会导致理想的和不良影响。因此，对药物 - 靶标的相互作用对于药物发现至关重要，以最大程度地提高治疗作用并最大程度地减少不良作用。比利时罗马尼亚比分直播

Conventional方法to identifying drug–target interactions (using biological experiments) were expensive and laborious, and have since been replaced with computational approaches. Due to their high efficiency and low costs, computational approaches have proved to be valuable methods for the prediction of drug–target interactions. Additionally, with advances in network pharmacology and systems biology, drug discovery approaches have drifted from the linear mode (one drug, one target and one disease approach) to the network mode (multi-drug, multi-target and multi-disease approach). This means that rather than selectively binding to one target, a single drug may work on multiple targets.

基于药效团预测药物 - 靶标相互作用的方法包括基于结构和基于配体的药剂团映射。基于结构的方法取决于three-dimensional (3D)structures of targets.博士Behnoush Hajian, research scientist II at the麻省理工学院和哈佛大学解释说：“基于结构的药物设计（SBDD）仍然是指导新治疗剂设计的关键工具。结构生物学的最新进展显着加速了获得与配体或铅化合物结合的药物靶标的3D结构的过程。SBDD允许我们更自信地探索新的化学探针并提高铅化合物的效力和选择性，以查看长期昂贵的药物发现运动的果实。”比利时罗马尼亚比分直播

分子对接是一个广泛使用的基于结构的在硅中method. Based on the 3D structures of targets, this method uses scoring functions to predict drug–target interactions and provides quantitative docking scores correlated with binding affinities. Ligand-based pharmacophore modeling如果没有目标结构，则使用有关活性配体与目标结合的结构信息。

Network-based methods预测通过多种算法重新定位的新型药物靶基因或药物. Compared to molecular docking-based methods, network-based methods are simple, fast and independent of the 3D structures of drug targets.

最近，还出现了各种用于目标识别的新型方法。热蛋白质组分析（TPP）是一种最近开发的工具，可以使用定量质谱法监测蛋白质热稳定性的变化。博士安德烈·马特斯（AndréMateus）Umeå大学化学系的助理教授解释说：“热蛋白质组分析（TPP）基于这样的原则：当蛋白质加热时，它们具有变性并变得不溶于作用。TPP是细胞热移测定法（CETSA）的延伸，该原理首先直接应用于细胞中。通过使用基于质谱的定量蛋白质组学，TPP可以确定生物系统（细胞，组织，生物流体）中每种蛋白质的热稳定性。”

“Any physical interaction of a protein with a ligand has the potential to alter its thermal stability. By monitoring proteome-wide thermal stability, it is possible to see which proteins change in thermal stability when cells or tissues are treated with a drug – those are likely to be the targets. Since the method is performed in cells, proteins maintain their natural environment. TPP is one of the only chemical biology methods that thus enables measuring drug–target engagement directly原位，”伴侣说。

Aside from this,机器学习深度学习技术正在迅速开发用于预测药物 - 目标相互作用的工具。

目标验证是药物发现的关键一步比利时罗马尼亚比分直播

lIKE目标识别，目标验证是药物发现的关键步骤。比利时罗马尼亚比分直播目标验证确保a molecular target is directly involved in a disease mechanism and that modulation of the target is likely to have a therapeutic effect.

目标验证可能涉及确定靶基因的遗传操作（敲低或过表达），从而产生假定靶标的药物耐药突变体，使用degradation-based tools to anticipate the effects of the target and monitoring signaling pathways downstream of the presumed target.

What are some recent trends in drug target identification?

Zdrazil详细阐述了药物靶标识别的一些最新趋势，“药物靶标识别的最新趋势是包括靶标 - 疾病关联的遗传证据，因为具有遗传证明的疾病关联的靶标似乎更多是成功的在提供有效的药物中。另一个不断扩展的领域是包括途径和网络信息，它帮助研究人员推断出没有直接遗传支持的基因的新疾病关联。此外，许多计算科学家正在利用来自生物信息学数据库的药物目标信息，例如chembl– which hosts mainly small molecule bioactivity data along with assay, target and lots of other types of information – as well as the打开目标平台，将遗传学，基因组学和其他数据整合到系统的药物靶标优先级。”