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Identification of Protein-Excipient Interaction Hotspots Using Computational Approaches.

ABSTRACT: 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.

SUBMITTER: Barata TS

PROVIDER: S-EPMC4926387 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Identification of Protein-Excipient Interaction Hotspots Using Computational Approaches.

Barata Teresa S TS Zhang Cheng C Dalby Paul A PA Brocchini Steve S Zloh Mire M

International journal of molecular sciences 20160601 6

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 pro ...[more]

PMID: 27258262

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Project description:Protein therapeutics typically require a concentrated protein formulation, which can lead to self-association and/or high viscosity due to protein-protein interaction (PPI). Excipients are often added to improve stability, bioavailability, and manufacturability of the protein therapeutics, but the selection of excipients often relies on trial and error. Therefore, understanding the excipient-protein interaction and its effect on non-specific PPI is important for rational selection of formulation development. In this study, we validate a general workflow based on the site identification by ligand competitive saturation (SILCS) technology, termed SILCS-Biologics, that can be applied to protein therapeutics for rational excipient selection. The National Institute of Standards and Technology monoclonal antibody (NISTmAb) reference along with the CNTO607 mAb is used as model antibody proteins to examine PPIs, and NISTmAb was used to further examine excipient-protein interactions, in silico. Metrics from SILCS include the distribution and predicted affinity of excipients, buffer interactions with the NISTmAb Fab, and the relation of the interactions to predicted PPI. Comparison with a range of experimental data showed multiple SILCS metrics to be predictive. Specifically, the number of favorable sites to which an excipient binds and the number of sites to which an excipient binds that are involved in predicted PPIs correlate with the experimentally determined viscosity. In addition, a combination of the number of binding sites and the predicted binding affinity is indicated to be predictive of relative protein stability. Comparison of arginine, trehalose, and sucrose, all of which give the highest viscosity in combination with analysis of B22 and kD and the SILCS metrics, indicates that higher viscosities are associated with a low number of predicted binding sites, with lower binding affinity of arginine leading to its anomalously high impact on viscosity. The present study indicates the potential for the SILCS-Biologics approach to be of utility in the rational design of excipients during biologics formulation.

Dataset Information

Identification of Protein-Excipient Interaction Hotspots Using Computational Approaches.

Publications

Identification of Protein-Excipient Interaction Hotspots Using Computational Approaches.

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