Physiological changes in the albumin-bound non-esterified free fatty acids critically influence heme/bilirubin binding properties of the protein: A comparative, in vitro, spectroscopic study using the endogenous biomolecules

Amoorahim, Mahtab; Ashrafi-Kooshk, Mohammad Reza; Esmaeili, Sajjad; Shahlaei, Mohsen; Moradi, Sajad; Khodarahmi, Reza

doi:10.1016/j.saa.2020.118298

Cited by 7 publications

(1 citation statement)

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“…Drugs are transported in the circulation either in a free form, dissolved in the aqueous phase of plasma, or complexed with plasma proteins in varying degrees [1,2]. This drug-protein binding is reversible in nature, and an equilibrium between the bound and free drug molecules exists [3,4]. Serum albumin is the most abundant circulatory protein in blood plasma and plays an important role in the transport and deportation of different types of endogenous and exogenous compounds to target cells [5,6].…”

Section: Introductionmentioning

confidence: 99%

PI3K/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies

Yang

Zhang

et al. 2022

Molecules

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Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow’s site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA–GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA–GDC-0941 complex was approximately 105 M−1, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.

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