*Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
Biochem J. 2014 Aug 1;461(3):349-69. doi: 10.1042/BJ20140240.
Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.
尽管经过一个世纪的控制和根除运动，疟疾仍然是世界上最具破坏性的疾病之一。我们曾经强大的治疗武器在与疟原虫寄生虫的战斗中逐渐失去优势，这种寄生虫快速发展和传播抗药性的能力阻碍了过去和现在的疟疾控制工作。寻找新的、有效的疟疾治疗方法现在是全球卫生的首要任务之一，这促使全球研究人员和制药财团之间增加了资金投入，并促进了开源合作。其结果是药物发现方法和技术的快速进步，出现了三种主要的抗疟药物开发方法：（i）基于化学的方法，（ii）基于靶标的方法，和（iii）基于细胞的方法。所有这三种方法的共同点是结构生物学提供信息和加速药物开发的独特能力。在可能的情况下，基于结构的药物发现（SBDD）是抗疟药物开发计划的基础，并且对抗疟药物的发展非常有价值。然而，随着我们对疟原虫生命周期和耐药性发展机制的理解不断扩大，SBDD 作为一个领域必须继续发展，以开发出符合新型抗疟治疗药物理想特征的化合物，并避免在临床前和临床阶段高淘汰率。在本综述中，我们旨在检查 SBDD 对抗疟药物开发工作的贡献，涵盖从发现靶点到优化先导化合物以及预防寄生虫耐药性的各个方面。最后，讨论了结构生物学，特别是高通量结构基因组学计划，在发现未来药物靶标方面的潜力。
