Laboratorio de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, Address Av. do Café, s/n - Vila Monte Alegre, SP, 14040-903, Ribeirão Preto, Brazil.
Programa de pós-graduação em Ciências Farmacêuticas da UEFS, Feira de santana, Brazil.
J Comput Aided Mol Des. 2021 Aug;35(8):871-882. doi: 10.1007/s10822-021-00403-8. Epub 2021 Jun 28.
Assessment of target druggability guided by search and characterization of hot spots is a pivotal step in early stages of drug-discovery. The raw output of FTMap provides the data to perform this task, but it relies on manual intervention to properly combine different sets of consensus sites, therefore allowing identification of hot spots and evaluation of strength, shape and distance among them. Thus, the user's previous experience on the target and the software has a direct impact on how data generated by FTMap server can be explored. DRUGpy plugin was developed to overcome this limitation. By automatically assembling and scoring all possible combinations of consensus sites, DRUGpy plugin provides FTMap users a straight-forward method to identify and characterize hot spots in protein targets. DRUGpy is available in all operating systems that support PyMOL software. DRUGpy promptly identifies and characterizes pockets that are predicted by FTMap to bind druglike molecules with high-affinity (druggable sites) or low-affinity (borderline sites) and reveals how protein conformational flexibility impacts on the target's druggability. The use of DRUGpy on the analysis of trypanothione reductases (TR), a validated drug target against trypanosomatids, showcases the usefulness of the plugin, and led to the identification of a druggable pocket in the conserved dimer interface present in this class of proteins, opening new perspectives to the design of selective inhibitors.
基于热点搜索和特征描述的靶标可药性评估是药物发现早期阶段的关键步骤。FTMap 的原始输出提供了执行此任务的数据，但它依赖于手动干预来正确组合不同的共识位点集，从而能够识别热点并评估它们之间的强度、形状和距离。因此，用户在目标和软件方面的先前经验直接影响如何探索 FTMap 服务器生成的数据。DRUGpy 插件就是为了克服这一局限性而开发的。通过自动组装和评分所有可能的共识位点组合，DRUGpy 插件为 FTMap 用户提供了一种直接的方法来识别和描述蛋白质靶标中的热点。DRUGpy 可在支持 PyMOL 软件的所有操作系统上使用。DRUGpy 可以快速识别和描述那些被 FTMap 预测为与类药性分子具有高亲和力（可成药性位点）或低亲和力（边缘性位点）结合的口袋，并揭示蛋白质构象灵活性如何影响靶标可成药性。在对三磷酸鸟苷还原酶（TR）的分析中使用 DRUGpy，这是一种针对原生动物的已验证药物靶标，展示了该插件的有用性，并确定了在这类蛋白质中保守二聚体界面上存在的一个可成药性口袋，为设计选择性抑制剂开辟了新的前景。
