Lead optimization

销售线索优化
  • 文章类型: Journal Article
    在过去的20年里,基于片段的药物发现(FBDD)已成为药物发现管道中的一种流行和综合方法,由于它能够将几种候选药物带入临床试验,其中一些甚至被批准并推向市场。已被证明特别适用于该方法的一类靶标由激酶代表,正如BRAF抑制剂vemurafenib的批准所证明的那样。在这一广泛多样的蛋白质中,蛋白激酶CK1δ是治疗几种广泛的神经退行性疾病的一个特别有趣的靶点,如老年痴呆症,帕金森病,和肌萎缩侧索硬化症.计算方法,例如分子对接,已经与实验技术一起常规并成功地应用于FBDD运动中,在命中发现和命中优化阶段。关于这一点,开源软件Autogrow,由Durrant实验室开发,是一种半自动计算协议,利用遗传算法和分子对接软件之间的组合进行从头药物设计和铅优化。在目前的工作中,我们介绍并讨论了Autogrow代码的修改版本,该代码基于所研究化合物的相互作用指纹和晶体参考之间的相似性实现了自定义评分功能。为了验证其性能,我们进行了从头和铅优化运行(如原始出版物中所述),根据预测的结合模式以及与标准自动生长方案相比的静电和形状相似性,评估我们基于指纹的方案产生与已知CK1δ抑制剂相似的化合物的能力。
    In the last 20 years, fragment-based drug discovery (FBDD) has become a popular and consolidated approach within the drug discovery pipeline, due to its ability to bring several drug candidates to clinical trials, some of them even being approved and introduced to the market. A class of targets that have proven to be particularly suitable for this method is represented by kinases, as demonstrated by the approval of BRAF inhibitor vemurafenib. Within this wide and diverse set of proteins, protein kinase CK1δ is a particularly interesting target for the treatment of several widespread neurodegenerative diseases, such as Alzheimer\'s disease, Parkinson\'s disease, and amyotrophic lateral sclerosis. Computational methodologies, such as molecular docking, are already routinely and successfully applied in FBDD campaigns alongside experimental techniques, both in the hit-discovery and in the hit-optimization stage. Concerning this, the open-source software Autogrow, developed by the Durrant lab, is a semi-automated computational protocol that exploits a combination between a genetic algorithm and a molecular docking software for de novo drug design and lead optimization. In the current work, we present and discuss a modified version of the Autogrow code that implements a custom scoring function based on the similarity between the interaction fingerprint of investigated compounds and a crystal reference. To validate its performance, we performed both a de novo and a lead-optimization run (as described in the original publication), evaluating the ability of our fingerprint-based protocol to generate compounds similar to known CK1δ inhibitors based on both the predicted binding mode and the electrostatic and shape similarity in comparison with the standard Autogrow protocol.
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