Barata Teresa S, Zhang Cheng, Dalby Paul A, Brocchini Steve, Zloh Mire
EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies, University College London, Biochemical Engineering Department, Bernard Katz Building, Gordon Street, London WC1H 0AH, UK.
UCL School of Pharmacy, Department of Pharmaceutics, 29-39 Brunswick Square, London WC1N 1AX, UK.
Int J Mol Sci. 2016 Jun 1;17(6):853. doi: 10.3390/ijms17060853.
Protein formulation development relies on the selection of excipients that inhibit protein-protein interactions preventing aggregation. Empirical strategies involve screening many excipient and buffer combinations using force degradation studies. Such methods do not readily provide information on intermolecular interactions responsible for the protective effects of excipients. This study describes a molecular docking approach to screen and rank interactions allowing for the identification of protein-excipient hotspots to aid in the selection of excipients to be experimentally screened. Previously published work with Drosophila Su(dx) was used to develop and validate the computational methodology, which was then used to determine the formulation hotspots for Fab A33. Commonly used excipients were examined and compared to the regions in Fab A33 prone to protein-protein interactions that could lead to aggregation. This approach could provide information on a molecular level about the protective interactions of excipients in protein formulations to aid the more rational development of future formulations.
蛋白质制剂的开发依赖于选择能够抑制蛋白质-蛋白质相互作用以防止聚集的辅料。经验性策略包括使用强制降解研究筛选多种辅料和缓冲液组合。此类方法无法轻易提供有关负责辅料保护作用的分子间相互作用的信息。本研究描述了一种分子对接方法，用于筛选和排列相互作用，从而识别蛋白质-辅料热点，以帮助选择待进行实验筛选的辅料。先前发表的关于果蝇Su(dx)的研究工作被用于开发和验证该计算方法，然后该方法被用于确定Fab A33的制剂热点。研究人员检查了常用辅料，并将其与Fab A33中易于发生可能导致聚集的蛋白质-蛋白质相互作用的区域进行了比较。这种方法可以在分子水平上提供有关蛋白质制剂中辅料保护相互作用的信息，以帮助更合理地开发未来的制剂。
