Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules

被引:18
作者
Iuzzolino, Luca [1 ]
Reilly, Anthony M. [2 ,3 ]
McCabe, Patrick [2 ]
Price, Sarah L. [1 ]
机构
[1] UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England
[2] Cambridge Crystallog Data Ctr, 12 Union Rd, Cambridge CB2 1EZ, England
[3] Dublin City Univ, Sch Chem Sci, Dublin 9, Ireland
基金
英国工程与自然科学研究理事会;
关键词
ENERGY LANDSCAPES; BLIND TEST; DENSITY; CRYSTALLIZATION; POLYMORPHISM; PREFERENCES; ANGLE;
D O I
10.1021/acs.jctc.7b00623
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.
引用
收藏
页码:5163 / 5171
页数:9
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