基于天然产物与靶标共晶结构的药物发现与优化

Drug discovery and optimization based on the co-crystal structure of natural product with target

基于天然产物与靶标共晶结构的药物发现与优化

Authors：Chen X, Varghese S, Zhang Z, Du J, Ruan B, Baell JB, Liu X.

Source：Eur J Med Chem. 

DOI: 10.1016/j.ejmech.2024.116126

Abstract

Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.

摘要

由于其结构多样性和普遍的生物活性，天然产物（NP）是药物发现的重要资源。尽管NP具有广泛的生物活性，但许多NPs表现出结构复杂性，导致合成困难，这与低效的生物活性、毒性和不利的药代动力学特征相结合，最终导致安全性和有效性结果较差。结晶和计算技术的进步使晶体学对药物发现产生了季节性的影响。通过与蛋白质共结晶，可以确定NPs在特定疾病中的治疗靶点。通过分析共晶信息，可以掌握靶向特定蛋白质的NP的构效关系（SAR）。在共晶信息的指导下，定向结构修饰和简化是克服NPs局限性、提高NP药物发现成功率、获得高选择性、低毒性和良好药代动力学特性的NP基药物的有力策略。本文综述了部分NPs的共晶信息，重点介绍了共晶信息所反映的NPs的SARs以及NPs的修饰和简化策略，并讨论了如何将共晶信息应用于NP基先导化合物的优化。