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Systematic Exploration of Activity Cliffs Containing Privileged Substructures.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-24 , DOI: 10.1021/acs.molpharmaceut.9b01236
Huabin Hu 1 , Jürgen Bajorath 1
Affiliation  

The privileged substructure (PS) and activity cliff (AC) concepts are popular in pharmaceutical research. PSs have been empirically identified as preferred building blocks for target-class-directed generation of active compounds. Although some PSs are controversially viewed, they continue to receive much attention in drug discovery. ACs are formed by structurally similar active compounds with large potency differences and thus capture structure-activity relationship (SAR) discontinuity and reveal SAR determinants. So far, the PS and AC concepts have not been investigated in context. We have systematically explored ACs formed by compounds containing different PSs (PS-ACs). Such ACs were frequently identified in different series of compounds. PS-ACs were thoroughly characterized and compared to ACs formed by other compounds. The analysis revealed differences in AC formation between PSs. For example, individual PSs with an unusually high proportion of AC-forming compounds were identified. Furthermore, PS-AC network analysis identified clusters of ACs containing the same PS in different compound structure contexts with activity against different targets. From such PS-AC clusters, target-specific SAR information for PSs in different structural environments can be extracted.

中文翻译:

包含特权子结构的活动悬崖的系统探索。

特权子结构(PS)和活动悬崖(AC)概念在药物研究中很流行。PS已被凭经验确定为目标化合物定向生成活性化合物的优选构件。尽管有些PS引起了争议,但它们在药物发现中继续受到很多关注。ACs是由结构相似的活性化合物形成的,这些活性化合物的效能差异很大,因此可以捕获结构活性关系(SAR)的不连续性并揭示SAR决定因素。到目前为止,尚未对上下文中的PS和AC概念进行研究。我们已经系统地研究了由含有不同PS的化合物(PS-AC)形成的AC。经常在不同系列的化合物中鉴定出此类AC。对PS-AC进行了彻底的表征,并与其他化合物形成的AC进行了比较。分析显示PS之间AC形成的差异。例如,鉴定出具有异常高比例的形成AC的化合物的单个PS。此外,PS-AC网络分析还确定了在不同化合物结构环境中含有相同PS且具有针对不同目标的活性的AC簇。从此类PS-AC群集中,可以提取不同结构环境中PS的目标特定SAR信息。
更新日期:2020-02-03
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