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The Role of Cyclodextrins against Interface-Induced Denaturation in Pharmaceutical Formulations: A Molecular Dynamics Approach.

ABSTRACT: Protein-based pharmaceutical products are subject to a variety of environmental stressors, during both production and shelf-life. In order to preserve their structure, and, therefore, functionality, it is necessary to use excipients as stabilizing agents. Among the eligible stabilizers, cyclodextrins (CDs) have recently gained interest in the scientific community thanks to their properties. Here, a computational approach is proposed to clarify the role of β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) against granulocyte colony-stimulating (GCSF) factor denaturation at the air-water and ice-water interfaces, and also in bulk water at 300 or 260 K. Both traditional molecular dynamics (MD) simulations and enhanced sampling techniques (metadynamics, MetaD) are used to shed light on the underlying molecular mechanisms. Bulk simulations revealed that CDs were preferentially included within the surface hydration layer of GCSF, and even included some peptide residues in their hydrophobic cavity. HPβCD was able to stabilize the protein against surface-induced denaturation in proximity of the air-water interface, while βCD had a destabilizing effect. No remarkable conformational changes of GCSF, or noticeable effect of the CDs, were instead observed at the ice surface. GCSF seemed less stable at low temperature (260 K), which may be attributed to cold-denaturation effects. In this case, CDs did not significantly improve conformational stability. In general, the conformationally altered regions of GCSF seemed not to depend on the presence of excipients that only modulated the extent of destabilization with either a positive or a negative effect.

SUBMITTER: Rospiccio M

PROVIDER: S-EPMC8289300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:2-[N-(carboxymethyl)anilino] acetic acid (PIDAA) molecule has been spectroscopically characterized and computationally investigated for its fundamental reactive properties by a combination of density functional theory (DFT) calculations, molecular dynamics (MD) simulations and molecular docking procedure. A comparison drawn between the simulated and experimentally attained spectra by FT-Raman and FT-IR showed concurrence. The natural bond orbital (NBO) analysis enabled in comprehending the stability and charge delocalization in the title molecule. The first hyperpolarizability which is an important parameter for future studies of nonlinear optics (NLO) was calculated to check the potential of the molecule to be an NLO material. Besides, frontier molecular orbitals (FMO), electron localization function (ELF) and localized orbital locator (LOL) analysis were performed. Energy gap (?E), electronegativity (?), chemical potential (?), global hardness (?), softness (S), Mulliken population analysis on atomic charges and thermodynamic properties of the title compound at different temperatures have been calculated. The local reactive properties of PIDAA have been addressed by MEP and ALIE surfaces, together with bond dissociation energy for hydrogen abstraction (H-BDE). MD simulations have been used in order to identify atoms with pronounced interactions with water molecules. The pharmaceutical potential of PIDAA has been considered by the analysis of drug likeness parameters and molecular docking procedure. The biological activity of the molecule in terms of molecular docking has been analyzed theoretically for the treatment of SARS and minimum binding energy calculated. The Ramachandran plot was used to check the stereochemistry of the protein structure. In addition, a comparison of the physiochemical parameters of PIDAA and commercially available drugs (Yu et al., 2004; Tan et al., 2004; Elshabrawy et al., 2014; Chu et al., 2004; Gopal Samy and Xavier, 2015) were carried out.

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The Role of Cyclodextrins against Interface-Induced Denaturation in Pharmaceutical Formulations: A Molecular Dynamics Approach.

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