Correlation between calculated molecular descriptors of excipient amino acids and experimentally observed thermal stability of lysozyme

TY - JOUR

T1 - Correlation between calculated molecular descriptors of excipient amino acids and experimentally observed thermal stability of lysozyme

AU - Meng-Lund, Helena

AU - Friis, Natascha

AU - van de Weert, Marco

AU - Rantanen, Jukka

AU - Poso, Antti

AU - Grohganz, Holger

AU - Jorgensen, Lene

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - A quantitative structure-property relationship (QSPR) between protein stability and the physicochemical properties of excipients was investigated to enable a more rational choice of stabilizing excipients than prior knowledge. The thermal transition temperature and aggregation time were determined for lysozyme in combination with 13 different amino acids using high throughput fluorescence spectroscopy and kinetic static light scattering measurements. On the theoretical side, around 200 2D and 3D molecular descriptors were calculated based on the amino acids' chemical structure. Multivariate data analysis was applied to correlate the descriptors with the experimental results. It was possible to identify descriptors, i.e. amino acids properties, with a positive influence on either transition temperature or aggregation onset time, or both. A high number of hydrogen bond acceptor moieties was the most prominent stabilizing factor for both responses, whereas hydrophilic surface properties and high molecular mass density mostly had a positive influence on the unfolding temperature. A high partition coefficient (logP(o/w)) was identified as the most prominent destabilizing factor for both responses. The QSPR shows good correlation between calculated molecular descriptors and the measured stabilizing effect of amino acids on lysozyme.

AB - A quantitative structure-property relationship (QSPR) between protein stability and the physicochemical properties of excipients was investigated to enable a more rational choice of stabilizing excipients than prior knowledge. The thermal transition temperature and aggregation time were determined for lysozyme in combination with 13 different amino acids using high throughput fluorescence spectroscopy and kinetic static light scattering measurements. On the theoretical side, around 200 2D and 3D molecular descriptors were calculated based on the amino acids' chemical structure. Multivariate data analysis was applied to correlate the descriptors with the experimental results. It was possible to identify descriptors, i.e. amino acids properties, with a positive influence on either transition temperature or aggregation onset time, or both. A high number of hydrogen bond acceptor moieties was the most prominent stabilizing factor for both responses, whereas hydrophilic surface properties and high molecular mass density mostly had a positive influence on the unfolding temperature. A high partition coefficient (logP(o/w)) was identified as the most prominent destabilizing factor for both responses. The QSPR shows good correlation between calculated molecular descriptors and the measured stabilizing effect of amino acids on lysozyme.

KW - Journal Article

U2 - 10.1016/j.ijpharm.2017.03.043

DO - 10.1016/j.ijpharm.2017.03.043

M3 - Journal article

C2 - 28336459

SN - 0378-5173

VL - 523

SP - 238

EP - 245

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

IS - 1

ER -