源自晶体结构数据的小分子构象偏好。一项聚焦于药物化学的分析。

Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis.

作者信息

Brameld Ken A, Kuhn Bernd, Reuter Deborah C, Stahl Martin

机构信息

Discovery Chemistry, Roche Palo Alto LLC, Palo Alto, California, USA.

出版信息

J Chem Inf Model. 2008 Jan;48(1):1-24. doi: 10.1021/ci7002494. Epub 2008 Jan 10.

Abstract

Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six- and seven-membered ring systems are discussed. The article closes with a section on attractive sulfur-oxygen contacts.

摘要

基于常见子结构的扭转角分布,展示了类药物分子的构象偏好,并对相关文献进行了综述。首先,通过比较进入临床试验的化合物中存在的子结构与剑桥结构数据库(CSD)中发现的子结构以及蛋白质数据库(PDB)中与蛋白质结合的配体,证明了CSD对药物设计的相关性。接下来,我们简要强调基本无环系统的优选构象,随后讨论磺酰胺构象。由于它们在药物化学中的核心作用,我们深入讨论芳环取代基的性质,包括联芳基系统以及由两个无环键连接的两个芳环的系统。对于一部分扭转基序,我们还比较了从CSD结构得出的扭转角直方图与从PDB中的配体得出的扭转角直方图。此外,还讨论了一些六元环和七元环系统的选定性质。文章最后一部分是关于有吸引力的硫 - 氧接触。

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