Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.
Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.
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DOI：
10.1002/cmdc.201500414
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发表时间：
2016-01-05
期刊：
影响因子：
3.4
通讯作者：
Abell C
中科院分区：
文献类型：
--
作者：
Hung AW;Silvestre HL;Wen S;George GP;Boland J;Blundell TL;Ciulli A;Abell C
配体效率已被证明是在药物设计的早期阶段优化先导化合物的有价值的概念。更进一步，群效率（GE）评估分子每个附属物的结合效率，进一步微调药物设计过程。在这里，GE分析用于系统地提高结核分枝杆菌泛酸合成酶抑制剂的效力，这是结核病治疗中的一个重要靶点。发现结合效率在使用基于片段的方法获得的先导分子内分布不均匀。取代分子中效率较低的部分，可以系统地开发出更有效的化合物。这种解剖和分析分子内不同基团的方法提供了进行先导物优化的合理和通用的方法，在药物发现中具有潜在的广泛应用。
Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine‐tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment‐based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.