文献类型：期刊文献

英文题名：Crystal Structure Prediction Synergizes with Crystallization Tendency Analysis: A Case Study in Polymorph Screening of a Novel PRMT5 Inhibitor

作者：Zhou, Yanfeng[1,2];Zhang, Yizu[3];Song, Zhengtian[3];Liu, Xiang[3];Yao, Jia[3];Zeng, Qun[3];Sun, Guangxu[3];Li, Mingxi[2];Yang, Zhuocen[3];Ma, Lei[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Shanghai Apeiron Therapeut Co Ltd, Unit C101, Shanghai 201210, Peoples R China;[3]XtalPi Inc, Shenzhen Jingtai Technol Co Ltd, Int Biomed Ind Pk,Phase 2,3F, Shenzhen 518038, Peoples R China

年份：2026

卷号：26

期号：9

起止页码：3388

外文期刊名：CRYSTAL GROWTH & DESIGN

收录：;EI(收录号：20261920663269);WOS:【SCI-EXPANDED(收录号:WOS:001736503300001)】；

基金：This work was supported by the National Natural Science Foundation of China (Grants 82373739) and the National Key Research and Development Project of China (Grants 2023YFA1802000).

语种：英文

外文关键词：Polymorphism - Thermodynamics

摘要：Polymorph screening is essential in pharmaceutical development to ensure the selection of optimal solid forms for active pharmaceutical ingredients. Here, we report an integrated crystal structure prediction and an experimental approach to map the polymorphic landscape of GTA182, a novel PRMT5 inhibitor. Computational energy landscape analysis identified low-energy structures corresponding to three experimentally observed anhydrous forms and revealed additional more stable forms not accessed by conventional screening. Although not the most thermodynamically stable form at room temperature, Form A emerged as the kinetically favored polymorph in crystallization experiments, a finding rationalized by a solution-based crystallization tendency analysis. Its predicted structure was confirmed by microcrystal electron diffraction (MicroED). This combined strategy guided targeted experimental screening, leading to the identification of 19 solid forms (anhydrates, hydrates, and solvates) and validating the predicted stability relationship between Forms A and O. The study establishes a practical workflow for derisking polymorph selection in drug development by providing critical insights into the interplay of thermodynamics and kinetics in crystalline form landscapes.