Back to the future: lessons learned in modern target-based and whole-cell lead optimization of antimalarials.
Back to the future: lessons learned in modern target-based and whole-cell lead optimization of antimalarials.
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DOI：
10.2174/156802612799362977
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发表时间：
2012
影响因子：
3.4
通讯作者：
Yeung BK
中科院分区：
文献类型：
--
作者：
Chatterjee AK;Yeung BK
抗疟药物的发现历来受益于全细胞（表型）筛选方法，以确定寻找新药的先导分子。然而，在过去的二十年里，制药行业已经从全细胞筛选转向基于靶点的方法。作为Wellcome Trust和Medicines for Malaria Venture（MMV）资助的发现新血液阶段抗疟药的财团的一部分，我们使用这两种方法来鉴定新的抗疟化学型，其中两种已经超越了先导优化阶段，并在小鼠中显示出优异的体内疗效。这两个先进的系列通过基于细胞的优化没有目标信息，在这篇评论中，我们总结了这种方法的优势与基于目标的优化。虽然每种电极导线优化需要略微不同的药物化学策略，但我们观察到不同支架的一些共同问题，这些问题可以应用于其他基于细胞的电极导线优化程序。
Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs.